Antifungal Compound Process

ABSTRACT

The present invention relates to a process for preparing a compound of 5 or 5*, or a mixture thereof, that is useful as an antifungal agent. In particular, the invention seeks to provide new methodology for preparing compounds 7, 7* and 11, 11* and substituted derivatives thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application of InternationalApplication No. PCT/US2016/052128 filed Sep. 16, 2016, which claims thebenefit of U.S. Provisional Application No. 62/220,384, filed Sep. 18,2015 and U.S. Provisional Application No. 62/275,504, filed Jan. 6,2016, each of which is incorporated herein by reference in its entirety.

BACKGROUND

Living organisms have developed tightly regulated processes thatspecifically import metals, transport them to intracellular storagesites and ultimately transport them to sites of use. One of the mostimportant functions of metals such as zinc and iron in biologicalsystems is to enable the activity of metalloenzymes. Metalloenzymes areenzymes that incorporate metal ions into the enzyme active site andutilize the metal as a part of the catalytic process. More thanone-third of all characterized enzymes are metalloenzymes.

The function of metalloenzymes is highly dependent on the presence ofthe metal ion in the active site of the enzyme. It is well recognizedthat agents which bind to and inactivate the active site metal iondramatically decrease the activity of the enzyme. Nature employs thissame strategy to decrease the activity of certain metalloenzymes duringperiods in which the enzymatic activity is undesirable. For example, theprotein TIMP (tissue inhibitor of metalloproteases) binds to the zincion in the active site of various matrix metalloprotease enzymes andthereby arrests the enzymatic activity. The pharmaceutical industry hasused the same strategy in the design of therapeutic agents. For example,the azole antifungal agents fluconazole and voriconazole contain a1-(1,2,4-triazole) group that binds to the heme iron present in theactive site of the target enzyme lanosterol demethylase and therebyinactivates the enzyme.

In the design of clinically safe and effective metalloenzyme inhibitors,use of the most appropriate metal-binding group for the particulartarget and clinical indication is critical. If a weakly bindingmetal-binding group is utilized, potency may be suboptimal. On the otherhand, if a very tightly binding metal-binding group is utilized,selectivity for the target enzyme versus related metalloenzymes may besuboptimal. The lack of optimal selectivity can be a cause for clinicaltoxicity due to unintended inhibition of these off-targetmetalloenzymes. One example of such clinical toxicity is the unintendedinhibition of human drug metabolizing enzymes such as CYP2C9, CYP2C19and CYP3A4 by the currently-available azole antifungal agents such asfluconazole and voriconazole. It is believed that this off-targetinhibition is caused primarily by the indiscriminate binding of thecurrently utilized 1-(1,2,4-triazole) to iron in the active site ofCYP2C9, CYP2C19 and CYP3A4. Another example of this is the joint painthat has been observed in many clinical trials of matrixmetalloproteinase inhibitors. This toxicity is considered to be relatedto inhibition of off-target metalloenzymes due to indiscriminate bindingof the hydroxamic acid group to zinc in the off-target active sites.

Therefore, the search for metal-binding groups that can achieve a betterbalance of potency and selectivity remains an important goal and wouldbe significant in the realization of therapeutic agents and methods toaddress currently unmet needs in treating and preventing diseases,disorders and symptoms thereof. Similarly, methods of synthesizing suchtherapeutic agents on the laboratory and, ultimately, commercial scaleis needed. Addition of metal-based nucleophiles (Zn, Zr, Ce, Ti, Mg, Mn,Li) to azole-methyl substituted ketones have been effected in thesynthesis of voriconazole (M. Butters, Org. Process Res. Dev. 2001, 5,28-36). The nucleophile in these examples was an ethyl-pyrimidinesubstrate. Similarly, optically active azole-methyl epoxide has beenprepared as precursor electrophile toward the synthesis of ravuconazole(A. Tsuruoka, Chem. Pharm. Bull. 1998, 46, 623-630). Despite this, thedevelopment of methodology with improved efficiency and selectivity isdesirable.

BRIEF SUMMARY OF THE INVENTION

The invention is directed toward methods of synthesis of compound 5 orcompound 5*. The methods can comprise the compounds herein. A firstaspect of the invention relates to a process for preparing a compound offormula 5 or 5*, or a pharmaceutically acceptable salt, hydrate,solvate, complex or prodrug thereof.

The compounds herein include those wherein the compound is identified asattaining affinity, at least in part, for a metalloenzyme by formationof one or more of the following types of chemical interactions or bondsto a metal: sigma bonds, covalent bonds, coordinate-covalent bonds,ionic bonds, pi bonds, delta bonds, or backbonding interactions.

Methods for assessing metal-ligand binding interactions are known in theart as exemplified in references including, for example, “Principles ofBioinorganic Chemistry” by Lippard and Berg, University Science Books,(1994); “Mechanisms of Inorganic Reactions” by Basolo and Pearson JohnWiley & Sons Inc; 2nd edition (September 1967); “Biological InorganicChemistry” by Ivano Bertini, Harry Gray, Ed Stiefel, Joan Valentine,University Science Books (2007); Xue et al. “Nature Chemical Biology”,vol. 4, no. 2, 107-109 (2008).

In the following aspects, reference is made to the schemes and compoundsherein, including the reagents and reaction conditions delineatedherein. Other aspects include any of the compounds, reagents,transformations or methods thereof delineated in the examples herein (inwhole or in part), including as embodiments with single elements (e.g.,compounds or transformations) or embodiments including multiple elements(e.g., compounds or transformations).

In one aspect, the invention provides a process to prepare a compound ofFormula 1 or 1*, or mixture thereof:

the process comprising reacting a compound of Formula 2:

with nitromethane in the presence of a chiral catalyst of Formula 3 or3*:

-   -   wherein each R₄ is independently H, optionally substituted        alkyl, (C═O)-optionally substituted alkyl, (C═O)-optionally        substituted aryl; and    -   each R₅ is independently H, optionally substituted alkyl,        optionally substituted arylalkyl, or optionally substituted        aryl;

to provide a compound of Formula 1 or 1*, or mixture thereof;

-   -   wherein each R is independently halo, —O(C═O)-alkyl,        —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted        aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl,        —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl,        —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, —O(SO₂)-substituted        aryl,

In another aspect, the invention provides a process to prepare acompound of Formula 1 or 1*, or mixture thereof:

the process comprising reacting a compound of Formula 2:

with nitromethane in the presence of a chiral catalyst of Formula 3:

-   -   wherein R₄ is H, optionally substituted alkyl, (C═O)-optionally        substituted alkyl, (C═O)-optionally substituted aryl; and    -   R₅ is H, optionally substituted alkyl, optionally substituted        arylalkyl, or optionally substituted aryl;

to provide a compound of Formula 1 or 1*, or mixture thereof;

-   -   wherein each R is independently halo, —O(C═O)-alkyl,        —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted        aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl,        —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl,        —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, —O(SO₂)-substituted        aryl,

In another aspect, the chiral catalyst is

In another aspect, the mole percent of

used in any of the processes presented herein is about 0.5-50. Inanother aspect, the mole percent of

used in any of the processes presented herein is about 0.5-25. Inanother aspect, the mole percent of

used in any of the processes presented herein is about 1-10. In anotheraspect, the mole percent of

used in any of the processes presented herein is about 5.

In another embodiment, the number of equivalents of nitromethane used inany of the processes presented herein is about 1-25. In another aspect,the number of equivalents of nitromethane used in any of the processespresented herein is about 5-15. In another aspect, the number ofequivalents of nitromethane used in any of the processes presentedherein is about 10.

In another embodiment, the invention provides a process for reducing acompound of Formula 1 or 1*, or mixture thereof:

to afford a compound of Formula 4 or 4*, or mixture thereof:

wherein each R is independently halo, —O(C═O)-alkyl, —O(C═O)-substitutedalkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl,—O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl,—O(SO₂)-alkyl, —O(SO₂)-substituted alkyl, —O(SO₂)-aryl,—O(SO₂)-substituted aryl,

In another embodiment, the invention provides a process to prepare acompound of Formula 5 or 5*, or mixture thereof:

the method comprising:

-   -   a. reacting a compound of Formula 6:

with nitromethane in the presence of a chiral catalyst of Formula 3 or3*:

-   -   wherein each R₄ is independently H, optionally substituted        alkyl, (C═O)-optionally substituted alkyl, (C═O)-optionally        substituted aryl; and    -   each R₅ is independently H, optionally substituted alkyl,        optionally substituted arylalkyl, or optionally substituted        aryl;

to provide a compound of Formula 7 or 7*, or mixture thereof; and

-   -   b. conversion of a compound of Formula 7 or 7*, or mixture        thereof, to a compound of Formula 5 or 5*, or mixture thereof;        -   wherein each R₂ is independently OCF₃ or OCH₂CF₃; and        -   each R₃ is independently halo, —O(C═O)-alkyl,            —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted            aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl,            —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl,            —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or            —O(SO₂)-substituted aryl.

In another embodiment, the invention provides a process to prepare acompound of Formula 5 or 5*, or mixture thereof:

the method comprising:

-   -   a. reacting a compound of Formula 6:

with nitromethane in the presence of a chiral catalyst of Formula 3:

-   -   wherein R₄ is H, optionally substituted alkyl, (C═O)-optionally        substituted alkyl, (C═O)-optionally substituted aryl; and    -   R₅ is H, optionally substituted alkyl, optionally substituted        arylalkyl, or optionally substituted aryl;

to provide a compound of Formula 7 or 7*, or mixture thereof; and

-   -   b. conversion of a compound of Formula 7 or 7*, or mixture        thereof, to a compound of Formula 5 or 5*, or mixture thereof;        -   wherein each R₂ is independently OCF₃ or OCH₂CF₃; and        -   each R₃ is independently halo, —O(C═O)-alkyl,            —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted            aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl,            —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl,            —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or            —O(SO₂)-substituted aryl.

In another aspect, any of the embodiments presented herein may comprise:

arylation of ester 9;

to afford ketone 6;

-   -   wherein each R₃ is independently halo, —O(C═O)-alkyl,        —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted        aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl,        —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl,        —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted        aryl.

In another aspect, the method comprises reacting ester 9 with

-   -   wherein M is Mg or MgX, Li, AlX₂; X is halogen, alkyl, or aryl;        and    -   R₃ is independently halo, —O(C═O)-alkyl, —O(C═O)-substituted        alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl,        —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl,        —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl, —O(SO₂)-substituted        alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted aryl. In another        aspect, M is Mg or MgX, and X is halogen.

In another aspect, any of the embodiments presented herein may comprise:

a. amidation of ester 9;

to afford morpholine amide 10; and

b. arylation of morpholine amide 10 to afford ketone 6;

-   -   wherein each R₃ is independently halo, —O(C═O)-alkyl,        —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted        aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl,        —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl,        —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted        aryl.

In another aspect, step b. comprises reacting morpholine amide 10 with

-   -   wherein M is Mg or MgX, Li, AlX₂; X is halogen, alkyl, or aryl;        and    -   R₃ is independently halo, —O(C═O)-alkyl, —O(C═O)-substituted        alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl,        —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl,        —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl, —O(SO₂)-substituted        alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted aryl. In another        aspect, M is Mg or MgX, and X is halogen.

In another aspect, any of the embodiments presented herein may comprise:

reducing a compound of Formula 7 or 7*, or mixture thereof:

to afford a compound of Formula 11 or 11*, or mixture thereof:

-   -   wherein each R₃ is independently halo, —O(C═O)-alkyl,        —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted        aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl,        —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl,        —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted        aryl.

In another aspect, any of the embodiments presented herein may comprise:

-   -   a. arylating a compound of Formula 11 or 11*, or mixture        thereof,

to afford a compound of Formula 12 or 12*,or mixture thereof; and

-   -   b. forming the tetrazole of a compound of Formula 12 or 12*, or        mixture thereof, to afford a compound of Formula 5 or 5*, or        mixture thereof;

-   -   -   wherein each R₂ is independently OCF₃ or OCH₂CF₃; and        -   each R₃ is independently halo, —O(C═O)-alkyl,            —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted            aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl,            —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl,            —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or            —O(SO₂)-substituted aryl.

In another aspect, any of the embodiments presented herein may comprise:

-   -   a. forming the tetrazole of a compound of Formula 11 or 11*, or        mixture thereof,

to afford a compound of Formula 13 or 13*, or mixture thereof; and

-   -   b. arylating a compound of Formula 13 or 13*, or mixture        thereof, to afford a compound of Formula 5 or 5*, or mixture        thereof;

-   -   -   wherein each R₂ is independently OCF₃ or OCH₂CF₃; and        -   each R₃ is independently halo, —O(C═O)-alkyl,            —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted            aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl,            —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl,            —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or            —O(SO₂)-substituted aryl.

In the aforementioned processes, “arylation” can be accomplished by anysuitable coupling reaction process (e.g., Grignard reaction, Heckcoupling, Negishi coupling, Suzuki coupling, Suzuki-Miyaura reaction,Kumada cross-coupling, Castro-Stephens coupling, Ullmann reaction,Weinreb ketone synthesis, Stille coupling, Stille-Kelly coupling, andthe like), including organometallic coupling reactions known in the art,including use of organoborane, organoboronate, organocopper,organopalladium, organonickel, organosilicon, organolead,organomagnesium, organoiron, organolithium, and/or organotin reagentsand methods known in the art.

In the asymmetric Henry reaction process step, in one aspect thereaction is performed (and catalyst selected) such that the enatiomericratio of products is greater than 50:50; greater than 60:40; greaterthan 72:25; greater than 80:20; greater than 85:15; greater than 90:10;greater than 95:5; or greater than 97:3.

In another aspect, the invention provides a process to prepare compound5 or 5*, or a mixture thereof:

comprising converting amide 15c:

to compound 5 or 5*, or mixtures thereof;

-   -   wherein R₁ is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl,        —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl,        —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl,        —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl, —O(SO₂)-substituted        alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted aryl;    -   each R₂ is independently OCF₃ or OCH₂CF₃;    -   A is N(OMe)Me, NR₈R₉, or

-   -   p is 1, 2, 3, or 4;    -   q is 1, 2, 3, or 4;    -   each R₈ and R₉ is independently H, alkyl, substituted alkyl,        aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

In another aspect, the invention provides a process to prepare compound5 or 5*, or a mixture thereof:

comprising converting amide 15c:

to compound 5 or 5*, or mixtures thereof;

-   -   wherein R₁ is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl,        —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl,        —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl,        —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl, —O(SO₂)-substituted        alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted aryl;    -   each R₂ is independently OCF₃ or OCH₂CF₃;    -   B is N(OMe)Me, NR₈R₉, or

-   -   X is O, NR₈, or S;    -   r is 2, 3, or 4;    -   s is 2, 3, or 4;    -   each R₈ and R₉ is independently H, alkyl, substituted alkyl,        aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

In another aspect, the invention provides a process to prepare compound5 or 5*, or a mixture thereof:

comprising converting morpholine amide 15b:

to compound 5 or 5*, or a mixture thereof;

-   -   wherein R₁ is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl,        —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl,        —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl,        —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl, —O(SO₂)-substituted        alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted aryl; and    -   each R₂ is independently OCF₃ or OCH₂CF₃.

In another aspect, the invention provides a process comprising reactingmorpholine amide 15b:

-   -   wherein M is Mg or MgX; and X is halogen;

to provide a compound of 5 or 5*, or a mixture thereof:

-   -   wherein R₁ is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl,        —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl,        —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl,        —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl, —O(SO₂)-substituted        alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted aryl; and    -   each R₂ is independently OCF₃ or OCH₂CF₃.

In another aspect, the invention provides a process comprising reactingmorpholine amide 15b:

-   -   wherein M is Mg or MgX, Li, AlX₂; and X is halogen, alkyl, or        aryl;

to provide compound 5 or 5*, or a mixture thereof:

-   -   wherein R₁ is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl,        —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl,        —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl,        —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl, —O(SO₂)-substituted        alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted aryl; and    -   each R₂ is independently OCF₃ or OCH₂CF₃.

In another aspect, any of the embodiments presented herein may compriseamidation of ester 15:

to provide morpholine amide 15b:

-   -   wherein each R₁ is independently halo, —O(C═O)-alkyl,        —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted        aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl,        —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl,        —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted        aryl.

In another aspect, any of the embodiments presented herein may compriseamidation of ester 15d:

to provide morpholine amide 15b:

-   -   wherein each R₁ is independently halo, —O(C═O)-alkyl,        —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted        aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl,        —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl,        —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted        aryl; and    -   R₈ is H, alkyl, substituted alkyl, aryl, substituted aryl,        heteroaryl, or substituted heteroaryl.

In another aspect, any of the embodiments presented herein may comprisereacting ester 15:

with morpholine to provide morpholine amide 15b:

-   -   wherein each R₁ is independently halo, —O(C═O)-alkyl,        —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted        aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl,        —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl,        —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted        aryl.

In another aspect, any of the embodiments presented herein may comprisea process of enriching the enantiomeric purity of an enantiomericcompound mixture (e.g., Compounds 7/7*, or a mixture thereof and/or11/11*, or a mixture thereof), comprising:

(i) crystallizing said enantiomeric compound mixture with a chiral acidin a suitable solvent or solvent mixture, wherein:

-   -   the suitable solvent or solvent mixture is selected from        acetonitrile, isopropanol, ethanol, water, methanol, or        combinations thereof;

(ii) isolating the enantio-enriched compound mixture; and

(iii) free-basing the enantio-enriched chiral salt mixture to providethe enantio-enriched compound mixture.

In another aspect, the process of enriching the enantiomeric purity ofan enantiomeric compound mixture further comprises reslurrying theenantio-enriched chiral salt mixture in a slurrying solvent or slurryingsolvent mixture.

In another aspect, the chiral acid from any embodiment presented hereinis selected from the group consisting of tartaric acid,di-benzoyltartaric acid, malic acid, camphoric acid, camphorsulfonicacid, ascorbic acid, and di-p-toluoyltartaric acid;

In another aspect, the suitable solvent or solvent mixture from anyembodiments presented herein is 1-propanol, 1-butanol, ethyl acetate,tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyltert-butylether, diethyl ether, dichloromethane, 1,4-dioxane,1,2-dimethoxyethane, isopropyl acetate, heptane, hexane, cyclohexane, oroctane, or combinations thereof.

In another aspect, the slurrying solvent solvent or slurrying solventmixture from any embodiments presented herein is 1-propanol, 1-butanol,ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyltert-butylether, diethyl ether, dichloromethane, 1,4-dioxane,1,2-dimethoxyethane, isopropyl acetate, heptane, hexane, cyclohexane, oroctane, or combinations thereof.

In another aspect, the suitable solvent or solvent mixture from anyembodiments presented herein is a) acetonitrile or b) a mixture ofacetonitrile and isopropanol. Alternatively, another aspect is where themixture of acetonitrile and methanol comprises 80-90% acetonitrile and10-20% isopropanol.

In another aspect, the slurrying solvent or slurrying solvent mixturefrom any embodiments presented herein is a) acetonitrile or b) a mixtureof acetonitrile and isopropanol. Alternatively, another aspect is wherethe mixture of acetonitrile and isopropanol comprises 80-90%acetonitrile and 10-20% isopropanol.

In another aspect, any of the embodiments presented herein furthercomprises a process to prepare a compound of formula 14 or 14*, or amixture thereof, comprising:

-   -   (i) combining compound 5 or 5*, or a mixture thereof, a sulfonic        acid

and a crystallization solvent or crystallization solvent mixture;

-   -   (ii) diluting the mixture from step (i) with a crystallization        co-solvent or crystallization co-solvent mixture; and    -   (iii) isolating a compound of formula 14 or 14*, or a mixture        thereof;        -   wherein each Z is independently aryl, substituted aryl,            alkyl, or substituted alkyl; and        -   each R₂ is independently OCF₃ or OCH₂CF₃.

In another aspect, Z from any of the embodiments presented herein isphenyl, p-tolyl, methyl, or ethyl.

In another aspect, the crystalization solvent or crystallization solventmixture from any of the embodiments presented herein is ethyl acetate,isopropyl acetate, ethanol, methanol, or acetonitrile, or combinationsthereof.

In another aspect, the crystallization co-solvent or crystallizationco-solvent mixture from any of the embodiments presented herein ispentane, methyl t-butylether, hexane, heptane, or toluene, orcombinations thereof.

In another aspect, any of the embodiments presented herein may compriserepeating the enantio-enrichment step(s) until desired level ofenantio-enrichment is attained.

In other aspects, the invention provides a compound of any of theformulae herein, wherein the compound inhibits (or is identified toinhibit) lanosterol demethylase (CYP51).

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of any formulae herein and a pharmaceuticallyacceptable carrier.

In other aspects, the invention provides a method of modulatingmetalloenzyme activity in a subject, comprising contacting the subjectwith a compound of any formulae herein, in an amount and underconditions sufficient to modulate metalloenzyme activity.

In one aspect, the invention provides a method of treating a subjectsuffering from or susceptible to a metalloenzyme-related disorder ordisease, comprising administering to the subject an effective amount ofa compound or pharmaceutical composition of any formulae herein.

In another aspect, the invention provides a method of treating a subjectsuffering from or susceptible to a metalloenzyme-related disorder ordisease, wherein the subject has been identified as in need of treatmentfor a metalloenzyme-related disorder or disease, comprisingadministering to said subject in need thereof, an effective amount of acompound or pharmaceutical composition of any formulae herein, such thatsaid subject is treated for said disorder.

In another aspect, the invention provides a method of treating a subjectsuffering from or susceptible to a metalloenzyme-mediated disorder ordisease, wherein the subject has been identified as in need of treatmentfor a metalloenzyme-mediated disorder or disease, comprisingadministering to said subject in need thereof, an effective amount of acompound or pharmaceutical composition of any formulae herein, such thatmetalloenzyme activity in said subject is modulated (e.g., downregulated, inhibited). In another aspect, the compounds delineatedherein preferentially target cancer cells over nontransformed cells.

DETAILED DESCRIPTION Definitions

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “diastereomers” refers to stereoisomers with two or morecenters of dissymmetry and whose molecules are not mirror images of oneanother.

The term “enantiomers” refers to two stereoisomers of a compound whichare non-superimposable mirror images of one another. An equimolarmixture of two enantiomers is called a “racemic mixture” or a“racemate”.

The term “isomers” or “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

The term “prodrug” includes compounds with moieties which can bemetabolized in vivo. Generally, the prodrugs are metabolized in vivo byesterases or by other mechanisms to active drugs. Examples of prodrugsand their uses are well known in the art (See, e.g., Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). The prodrugs can beprepared in situ during the final isolation and purification of thecompounds, or by separately reacting the purified compound in its freeacid form or hydroxyl with a suitable esterifying agent. Hydroxyl groupscan be converted into esters via treatment with a carboxylic acid.Examples of prodrug moieties include substituted and unsubstituted,branch or unbranched lower alkyl ester moieties, (e.g., propionoic acidesters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters(e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g.,acetyloxymethyl ester), acyloxy lower alkyl esters (e.g.,pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkylesters (e.g., benzyl ester), substituted (e.g., with methyl, halo, ormethoxy substituents) aryl and aryl-lower alkyl esters, amides,lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferredprodrug moieties are propionoic acid esters and acyl esters. Prodrugswhich are converted to active forms through other mechanisms in vivo arealso included. In aspects, the compounds of the invention are prodrugsof any of the formulae herein.

The term “subject” refers to animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like. In certain embodiments, thesubject is a human.

The terms “a”, “an”, and “the” refer to “one or more” when used in thisapplication, including the claims. Thus, for example, reference to “asample” includes a plurality of samples, unless the context clearly isto the contrary (e.g., a plurality of samples), and so forth.

Throughout this specification and the claims, the words “comprise”,“comprises”, and “comprising” are used in a non-exclusive sense, exceptwhere the context requires otherwise.

As used herein, the term “about”, when referring to a value is meant toencompass variations of, in some embodiments ±20%, in some embodiments±10%, in some embodiments ±5%, in some embodiments ±1%, in someembodiments ±0.5%, and in some embodiments ±0.1% from the specifiedamount, as such variations are appropriate to perform the disclosedmethods or employ the disclosed compositions.

Use of the word “inhibitor” herein is meant to mean a molecule thatexhibits activity for inhibiting a metalloenzyme. By “inhibit” herein ismeant to decrease the activity of metalloenzyme, as compared to theactivity of metalloenzyme in the absence of the inhibitor. In someembodiments, the term “inhibit” means a decrease in metalloenzymeactivity of at least about 5%, at least about 10%, at least about 20%,at least about 25%, at least about 50%, at least about 60%, at leastabout 70%, at least about 80%, at least about 90%, or at least about95%. In other embodiments, inhibit means a decrease in metalloenzymeactivity of about 5% to about 25%, about 25% to about 50%, about 50% toabout 75%, or about 75% to 100%. In some embodiments, inhibit means adecrease in metalloenzyme activity of about 95% to 100%, e.g., adecrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such decreasescan be measured using a variety of techniques that would be recognizableby one of skill in the art. Particular assays for measuring individualactivity are described below.

Furthermore, the compounds of the invention include olefins havingeither geometry: “Z” refers to what is referred to as a “cis” (sameside) configuration whereas “E” refers to what is referred to as a“trans” (opposite side) configuration. With respect to the nomenclatureof a chiral center, the terms “d” and “l” configuration are as definedby the IUPAC Recommendations. As to the use of the terms, diastereomer,racemate, epimer and enantiomer, these will be used in their normalcontext to describe the stereochemistry of preparations.

As used herein, the term “alkyl” refers to a straight-chained orbranched hydrocarbon group containing 1 to 12 carbon atoms. The term“lower alkyl” refers to a C1-C6 alkyl chain. Examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, tent-butyl, and n-pentyl.Alkyl groups may be optionally substituted with one or moresubstituents.

The term “alkenyl” refers to an unsaturated hydrocarbon chain that maybe a straight chain or branched chain, containing 2 to 12 carbon atomsand at least one carbon-carbon double bond. Alkenyl groups may beoptionally substituted with one or more substituents.

The term “alkynyl” refers to an unsaturated hydrocarbon chain that maybe a straight chain or branched chain, containing the 2 to 12 carbonatoms and at least one carbon-carbon triple bond. Alkynyl groups may beoptionally substituted with one or more substituents.

The sp² or sp carbons of an alkenyl group and an alkynyl group,respectively, may optionally be the point of attachment of the alkenylor alkynyl groups.

The term “alkoxy” refers to an —O-alkyl radical.

As used herein, the term “halogen”, “hal” or “halo” means —F, —Cl, —Bror —I.

The term “haloalkoxy” refers to an —O-alkyl radical that is substitutedby one or more halo substituents. Examples of haloalkoxy groups includetrifluoromethoxy and 2,2,2-trifluoroethoxy.

The term “cycloalkyl” refers to a hydrocarbon 3-8 membered monocyclic or7-14 membered bicyclic ring system having at least one saturated ring orhaving at least one non-aromatic ring, wherein the non-aromatic ring mayhave some degree of unsaturation. Cycloalkyl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a cycloalkyl group may be substituted by asubstituent. Representative examples of cycloalkyl group includecyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and thelike.

The term “aryl” refers to a hydrocarbon monocyclic, bicyclic ortricyclic aromatic ring system. Aryl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by asubstituent. Examples of aryl groups include phenyl, naphthyl,anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-4 ring heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andthe remainder ring atoms being carbon (with appropriate hydrogen atomsunless otherwise indicated). Heteroaryl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a heteroaryl group may be substituted by asubstituent. Examples of heteroaryl groups include pyridyl, furanyl,thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl thiazolyl,isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and thelike.

The term “nitrogen-containing heteroaryl” refers to a heteroaryl grouphaving 1-4 ring nitrogen heteroatoms if monocyclic, 1-6 ring nitrogenheteroatoms if bicyclic, or 1-9 ring nitrogen heteroatoms if tricyclic.

The term “heterocycloalkyl” refers to a nonaromatic 3-8 memberedmonocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ringsystem comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, S, B, P or Si, wherein the nonaromatic ring system iscompletely saturated. Heterocycloalkyl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a heterocycloalkyl group may besubstituted by a substituent. Representative heterocycloalkyl groupsinclude piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl,thienyl, and the like.

The term “alkylamino” refers to an amino substituent which is furthersubstituted with one or two alkyl groups. The term “aminoalkyl” refersto an alkyl substituent which is further substituted with one or moreamino groups. The term “hydroxyalkyl” or “hydroxylalkyl” refers to analkyl substituent which is further substituted with one or more hydroxylgroups. The alkyl or aryl portion of alkylamino, aminoalkyl,mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl,sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionallysubstituted with one or more substituents.

Acids and bases useful in the methods herein are known in the art. Acidcatalysts are any acidic chemical, which can be inorganic (e.g.,hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic(e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid,ytterbium triflate) in nature. Acids are useful in either catalytic orstoichiometric amounts to facilitate chemical reactions. Bases are anybasic chemical, which can be inorganic (e.g., sodium bicarbonate,potassium hydroxide) or organic (e.g., triethylamine, pyridine) innature. Bases are useful in either catalytic or stoichiometric amountsto facilitate chemical reactions.

Alkylating agents are any reagent that is capable of effecting thealkylation of the functional group at issue (e.g., oxygen atom of analcohol, nitrogen atom of an amino group). Alkylating agents are knownin the art, including in the references cited herein, and include alkylhalides (e.g., methyl iodide, benzyl bromide or chloride), alkylsulfates (e.g., methyl sulfate), or other alkyl group-leaving groupcombinations known in the art. Leaving groups are any stable speciesthat can detach from a molecule during a reaction (e.g., eliminationreaction, substitution reaction) and are known in the art, including inthe references cited herein, and include halides (e.g., I—, Cl—, Br—,F—), hydroxy, alkoxy (e.g., —OMe, —O-t-Bu), acyloxy anions (e.g., —OAc,—OC(O)CF₃), sulfonates (e.g., mesyl, tosyl), acetamides (e.g.,—NHC(O)Me), carbamates (e.g., N(Me)C(O)Ot-Bu), phosphonates (e.g.,—OP(O)(OEt)₂), water or alcohols (protic conditions), and the like.

In certain embodiments, substituents on any group (such as, for example,alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, heterocycloalkyl) can be at any atom of that group, whereinany group that can be substituted (such as, for example, alkyl, alkenyl,alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl,heterocycloalkyl) can be optionally substituted with one or moresubstituents (which may be the same or different), each replacing ahydrogen atom. Examples of suitable substituents include, but are notlimited to alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano,nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl),carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl,thio, mercapto, mercaptoalkyl, aryl sulfonyl, amino, aminoalkyl,dialkylamino, alkylcarbonylamino, alkylaminocarbonyl,alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl,or arylamino-substituted aryl; arylalkylamino, aralkylaminocarbonyl,amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, imino, carbamido, carbamyl,thioureido, thiocyanato, sulfoamido, sulfonylalkyl, sulfonylaryl,mercaptoalkoxy, N-hydroxyamidinyl, or N′-aryl, N″-hydroxyamidinyl.

Compounds of the invention can be made by means known in the art oforganic synthesis. Methods for optimizing reaction conditions, ifnecessary minimizing competing by-products, are known in the art.Reaction optimization and scale-up may advantageously utilize high-speedparallel synthesis equipment and computer-controlled microreactors (e.g.Design And Optimization in Organic Synthesis, 2^(nd) Edition, Carlson R,Ed, 2005; Elsevier Science Ltd.; Jahnisch, K et al, Angew. Chem. Int.Ed. Engl. 2004 43: 406; and references therein). Additional reactionschemes and protocols may be determined by the skilled artesian by useof commercially available structure-searchable database software, forinstance, SciFinder® (CAS division of the American Chemical Society) andCrossFire Beilstein® (Elsevier MDL), or by appropriate keyword searchingusing an internet search engine such as Google® or keyword databasessuch as the US Patent and Trademark Office text database. The inventionincludes the intermediate compounds used in making the compounds of theformulae herein as well as methods of making such compounds andintermediates, including without limitation those as specificallydescribed in the examples herein.

The compounds herein may also contain linkages (e.g., carbon-carbonbonds) wherein bond rotation is restricted about that particularlinkage, e.g. restriction resulting from the presence of a ring ordouble bond. Accordingly, all cis/trans and E/Z isomers are expresslyincluded in the present invention. The compounds herein may also berepresented in multiple tautomeric forms, in such instances, theinvention expressly includes all tautomeric forms of the compoundsdescribed herein, even though only a single tautomeric form may berepresented. All such isomeric forms of such compounds herein areexpressly included in the present invention. All crystal forms andpolymorphs of the compounds described herein are expressly included inthe present invention. Also embodied are extracts and fractionscomprising compounds of the invention. The term isomers is intended toinclude diastereoisomers, enantiomers, regioisomers, structural isomers,rotational isomers, tautomers, and the like. For compounds which containone or more stereogenic centers, e.g., chiral compounds, the methods ofthe invention may be carried out with an enantiomerically enrichedcompound, a racemate, or a mixture of diastereomers.

Preferred enantiomerically enriched compounds have an enantiomericexcess of 50% or more, more preferably the compound has an enantiomericexcess of 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more. In preferredembodiments, only one enantiomer or diastereomer of a chiral compound ofthe invention is administered to cells or a subject.

Pharmaceutical Compositions

In one aspect, the invention provides a pharmaceutical compositioncomprising a compound of any formulae herein and a pharmaceuticallyacceptable carrier.

In another embodiment, the invention provides a pharmaceuticalcomposition further comprising an additional therapeutic agent. In afurther embodiment, the additional therapeutic agent is an anti-canceragent, antifungal agent, cardiovascular agent, antiinflammatory agent,chemotherapeutic agent, an anti-angiogenesis agent, cytotoxic agent, ananti-proliferation agent, metabolic disease agent, opthalmologic diseaseagent, central nervous system (CNS) disease agent, urologic diseaseagent, or gastrointestinal disease agent.

In one aspect, the invention provides a kit comprising an effectiveamount of a compound of any formulae herein, in unit dosage form,together with instructions for administering the compound to a subjectsuffering from or susceptible to a metalloenzyme-mediated disease ordisorder, including cancer, solid tumor, cardiovascular disease,inflammatory disease, infectious disease. In other embodiments thedisease, disorder or symptom thereof is metabolic disease, opthalmologicdisease, central nervous system (CNS) disease, urologic disease, orgastrointestinal disease.

The term “pharmaceutically acceptable salts” or “pharmaceuticallyacceptable carrier” is meant to include salts of the active compoundswhich are prepared with relatively nontoxic acids or bases, depending onthe particular substituents found on the compounds described herein.When compounds of the present invention contain relatively acidicfunctionalities, base addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredbase, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable base addition salts include sodium,potassium, calcium, ammonium, organic amino, or magnesium salt, or asimilar salt. When compounds of the present invention contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like (see, e.g., Berge et al.,Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts. Other pharmaceutically acceptable carriersknown to those of skill in the art are suitable for the presentinvention.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

The invention also provides a pharmaceutical composition, comprising aneffective amount a compound described herein and a pharmaceuticallyacceptable carrier. In an embodiment, compound is administered to thesubject using a pharmaceutically-acceptable formulation, e.g., apharmaceutically-acceptable formulation that provides sustained deliveryof the compound to a subject for at least 12 hours, 24 hours, 36 hours,48 hours, one week, two weeks, three weeks, or four weeks after thepharmaceutically-acceptable formulation is administered to the subject.

Actual dosage levels and time course of administration of the activeingredients in the pharmaceutical compositions of this invention may bevaried so as to obtain an amount of the active ingredient which iseffective to achieve the desired therapeutic response for a particularpatient, composition, and mode of administration, without being toxic(or unacceptably toxic) to the patient.

In use, at least one compound according to the present invention isadministered in a pharmaceutically effective amount to a subject in needthereof in a pharmaceutical carrier by intravenous, intramuscular,subcutaneous, or intracerebro-ventricular injection or by oraladministration or topical application. In accordance with the presentinvention, a compound of the invention may be administered alone or inconjunction with a second, different therapeutic. By “in conjunctionwith” is meant together, substantially simultaneously or sequentially.In one embodiment, a compound of the invention is administered acutely.The compound of the invention may therefore be administered for a shortcourse of treatment, such as for about 1 day to about 1 week. In anotherembodiment, the compound of the invention may be administered over alonger period of time to ameliorate chronic disorders, such as, forexample, for about one week to several months depending upon thecondition to be treated.

By “pharmaceutically effective amount” as used herein is meant an amountof a compound of the invention, high enough to significantly positivelymodify the condition to be treated but low enough to avoid serious sideeffects (at a reasonable benefit/risk ratio), within the scope of soundmedical judgment. A pharmaceutically effective amount of a compound ofthe invention will vary with the particular goal to be achieved, the ageand physical condition of the patient being treated, the severity of theunderlying disease, the duration of treatment, the nature of concurrenttherapy and the specific compound employed. For example, atherapeutically effective amount of a compound of the inventionadministered to a child or a neonate will be reduced proportionately inaccordance with sound medical judgment. The effective amount of acompound of the invention will thus be the minimum amount which willprovide the desired effect.

A decided practical advantage of the present invention is that thecompound may be administered in a convenient manner such as byintravenous, intramuscular, subcutaneous, oral orintra-cerebroventricular injection routes or by topical application,such as in creams or gels. Depending on the route of administration, theactive ingredients which comprise a compound of the invention may berequired to be coated in a material to protect the compound from theaction of enzymes, acids and other natural conditions which mayinactivate the compound. In order to administer a compound of theinvention by other than parenteral administration, the compound can becoated by, or administered with, a material to prevent inactivation.

The compound may be administered parenterally or intraperitoneally.Dispersions can also be prepared, for example, in glycerol, liquidpolyethylene glycols, and mixtures thereof, and in oils.

Some examples of substances which can serve as pharmaceutical carriersare sugars, such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethycellulose, ethylcellulose and cellulose acetates; powderedtragancanth; malt; gelatin; talc; stearic acids; magnesium stearate;calcium sulfate; vegetable oils, such as peanut oils, cotton seed oil,sesame oil, olive oil, corn oil and oil of theobroma; polyols such aspropylene glycol, glycerine, sorbitol, manitol, and polyethylene glycol;agar; alginic acids; pyrogen-free water; isotonic saline; and phosphatebuffer solution; skim milk powder; as well as other non-toxic compatiblesubstances used in pharmaceutical formulations such as Vitamin C,estrogen and echinacea, for example. Wetting agents and lubricants suchas sodium lauryl sulfate, as well as coloring agents, flavoring agents,lubricants, excipients, tableting agents, stabilizers, anti-oxidants andpreservatives, can also be present. Solubilizing agents, including forexample, cremaphore and beta-cyclodextrins can also used in thepharmaceutical compositions herein.

Pharmaceutical compositions comprising the active compounds of thepresently disclosed subject matter (or prodrugs thereof) can bemanufactured by means of conventional mixing, dissolving, granulating,dragee-making levigating, emulsifying, encapsulating, entrapping orlyophilization processes. The compositions can be formulated inconventional manner using one or more physiologically acceptablecarriers, diluents, excipients or auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically.

Pharmaceutical compositions of the presently disclosed subject mattercan take a form suitable for virtually any mode of administration,including, for example, topical, ocular, oral, buccal, systemic, nasal,injection, transdermal, rectal, vaginal, and the like, or a formsuitable for administration by inhalation or insufflation.

For topical administration, the active compound(s) or prodrug(s) can beformulated as solutions, gels, ointments, creams, suspensions, and thelike.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal, oral, or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions also can contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection canbe presented in unit dosage form (e.g., in ampules or in multidosecontainers) and can contain added preservatives.

Alternatively, the injectable formulation can be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, dextrose solution, and the like,before use. To this end, the active compound(s) can be dried by anyart-known technique, such as lyophilization, and reconstituted prior touse.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions can take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate). The tablets can be coated by methods well known in theart with, for example, sugars or enteric coatings.

Liquid preparations for oral administration can take the form of, forexample, elixirs, solutions, syrups or suspensions, or they can bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations can be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol or fractionated vegetable oils); and preservatives (e.g., methylor propyl p-hydroxybenzoates or sorbic acid). The preparations also cancontain buffer salts, preservatives, flavoring, coloring and sweeteningagents as appropriate.

Preparations for oral administration can be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions can take the form of tabletsor lozenges formulated in a conventional manner.

For rectal and vaginal routes of administration, the active compound(s)can be formulated as solutions (for retention enemas), suppositories, orointments containing conventional suppository bases, such as cocoabutter or other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit canbe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound or prodrug (0.5-20mg/ml); benzalkonium chloride (0.1-0.2 mg/mL); polysorbate 80 (TWEEN°80; 0.5-5 mg/ml); carboxymethylcellulose sodium or microcrystallinecellulose (1-15 mg/ml); phenylethanol (1-4 mg/ml); and dextrose (20-50mg/ml). The pH of the final suspension can be adjusted to range fromabout pH 5 to pH 7, with a pH of about pH 5.5 being typical.

For prolonged delivery, the active compound(s) or prodrug(s) can beformulated as a depot preparation for administration by implantation orintramuscular injection. The active ingredient can be formulated withsuitable polymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptioncan be used. To this end, permeation enhancers can be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. Nos. 5,407,713;5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189;5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, each of whichis incorporated herein by reference in its entirety.

Alternatively, other pharmaceutical delivery systems can be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat can be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) also can be employed.

The pharmaceutical compositions can, if desired, be presented in a packor dispenser device which can contain one or more unit dosage formscontaining the active compound(s). The pack can, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice can be accompanied by instructions for administration.

The active compound(s) or prodrug(s) of the presently disclosed subjectmatter, or compositions thereof, will generally be used in an amounteffective to achieve the intended result, for example in an amounteffective to treat or prevent the particular disease being treated. Thecompound(s) can be administered therapeutically to achieve therapeuticbenefit or prophylactically to achieve prophylactic benefit. Bytherapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated and/or eradication or amelioration ofone or more of the symptoms associated with the underlying disorder suchthat the patient reports an improvement in feeling or condition,notwithstanding that the patient can still be afflicted with theunderlying disorder. For example, administration of a compound to apatient suffering from an allergy provides therapeutic benefit not onlywhen the underlying allergic response is eradicated or ameliorated, butalso when the patient reports a decrease in the severity or duration ofthe symptoms associated with the allergy following exposure to theallergen. As another example, therapeutic benefit in the context ofasthma includes an improvement in respiration following the onset of anasthmatic attack, or a reduction in the frequency or severity ofasthmatic episodes. Therapeutic benefit also includes halting or slowingthe progression of the disease, regardless of whether improvement isrealized.

For prophylactic administration, the compound can be administered to apatient at risk of developing one of the previously described diseases.A patient at risk of developing a disease can be a patient havingcharacteristics placing the patient in a designated group of at riskpatients, as defined by an appropriate medical professional or group. Apatient at risk may also be a patient that is commonly or routinely in asetting where development of the underlying disease that may be treatedby administration of a metalloenzyme inhibitor according to theinvention could occur. In other words, the at risk patient is one who iscommonly or routinely exposed to the disease or illness causingconditions or may be acutely exposed for a limited time. Alternatively,prophylactic administration can be applied to avoid the onset ofsymptoms in a patient diagnosed with the underlying disorder.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, the bioavailability ofthe particular active compound, and the like. Determination of aneffective dosage is well within the capabilities of those skilled in theart.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC50 of the particular compound as measured in asin vitro assay, such as the in vitro fungal MIC or MFC and other invitro assays described in the Examples section. Calculating dosages toachieve such circulating blood or serum concentrations taking intoaccount the bioavailability of the particular compound is well withinthe capabilities of skilled artisans. For guidance, see Fingl &Woodbury, “General Principles,” In: Goodman and Gilman's ThePharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latestedition, Pagamonon Press, and the references cited therein, which areincorporated herein by reference.

Initial dosages also can be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art.

Dosage amounts will typically be in the range of from about 0.0001 or0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but can be higher orlower, depending upon, among other factors, the activity of thecompound, its bioavailability, the mode of administration, and variousfactors discussed above. Dosage amount and interval can be adjustedindividually to provide plasma levels of the compound(s) which aresufficient to maintain therapeutic or prophylactic effect. In cases oflocal administration or selective uptake, such as local topicaladministration, the effective local concentration of active compound(s)cannot be related to plasma concentration. Skilled artisans will be ableto optimize effective local dosages without undue experimentation.

The compound(s) can be administered once per day, a few or several timesper day, or even multiple times per day, depending upon, among otherthings, the indication being treated and the judgment of the prescribingphysician.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) can be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) effect isthe therapeutic index. Compounds(s) that exhibit high therapeuticindices are preferred.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof. Therecitation of an embodiment herein includes that embodiment as anysingle embodiment or in combination with any other embodiments orportions thereof.

Another object of the present invention is the use of a compound asdescribed herein (e.g., of any formulae herein) in the manufacture of amedicament for use in the treatment of a metalloenzyme-mediated disorderor disease. Another object of the present invention is the use of acompound as described herein (e.g., of any formulae herein) for use inthe treatment of a metalloenzyme-mediated disorder or disease. Anotherobject of the present invention is the use of a compound as describedherein (e.g., of any formulae herein) in the manufacture of anagricultural composition for use in the treatment or prevention of ametalloenzyme-mediated disorder or disease in agricultural or agrariansettings.

Agricultural Applications

The compounds and compositions herein can be used in methods ofmodulating metalloenzyme activity in a microorganism on a plantcomprising contacting a compound (or composition) herein with the plant(e.g., seed, seedling, grass, weed, grain). The compounds andcompositions herein can be used to treat a plant, field or otheragricultural area (e.g., as herbicides, pesticides, growth regulators,etc.) by administering the compound or composition (e.g., contacting,applying, spraying, atomizing, dusting, etc.) to the subject plant,field or other agricultural area. The administration can be either pre-or post-emergence. The administration can be either as a treatment orpreventative regimen.

EXAMPLES

The present invention will now be demonstrated using specific examplesthat are not to be construed as limiting.

General Experimental Procedures

Definitions of variables in the structures in schemes herein arecommensurate with those of corresponding positions in the formulaedelineated herein.

Synthesis of 5 or 5*

-   -   wherein each R₂ is independently OCF₃ or OCH₂CF₃.

A process to prepare enantiopure compound 5 or 5* is disclosed.Syntheses of 5 or 5* may be accomplished using the example synthesesthat are shown below (Schemes 1-4). The preparation of precursor ketone16-Br is performed starting with reaction of 2,5-dibromopyridine withethyl 2-bromo-difluoroacetate to produce ester 15-Br. This ester can bereacted with morpholine to furnish morpholine amide 15b-Br, followed byarylation to provide ketone 16-Br. Alternatively, ketone 16-Br can beafforded directly from ester 15-Br, as shown in Scheme 1.

Ketone 16 may be prepared in an analogous fashion as described in Scheme1 starting from corresponding substituted 2-bromo-pyridines, which canbe prepared according to synthetic transformations known in the art andcontained in the references cited herein (Scheme 2).

Ketone 16 may be used to prepare 13 (or 13*, the enantiomer of 13, ormixtures thereof) or 5 (or 5*, the enantiomer of 5, or mixtures thereof)by the following three-step process (Scheme 3). In the presence of achiral catalyst/reagent (e.g. compounds of Formula 3 or 3*),base-treated nitromethane is added to 16 or 16-1 to furnish 7 (or 7*,the enantiomer of 7, or mixtures thereof) or 7-1 (or 7*-1, theenantiomer of 7-1, or mixtures thereof), respectively. Reduction of 7(or 7*, the enantiomer of 7, or mixtures thereof) or 7-1 (or 7*-1, theenantiomer of 7-1, or mixtures thereof) (e.g. hydrogenation) produces 11(or 11*, the enantiomer of 11, or mixtures thereof) or 4 (or 4*, theenantiomer of 4, or mixtures thereof). Annulation of 11 (or 11*, theenantiomer of 11, or mixtures thereof) or 4 (or 4*, the enantiomer of 4,or mixtures thereof) by treatment with sodium azide/triethylorthoformatefurnishes tetrazoles 13 (or 13*, the enantiomer of 13, or mixturesthereof) or 5 (or 5*, the enantiomer of 5, or mixtures thereof). Suzukicoupling of 13 or 13* (e.g., 13 or 13*, wherein R═Br; also referred toas 13-Br or 13*-Br) with 4-trifluoromethoxyphenyl-boronic acid or4-trifluoroethoxyphenyl-boronic acid produces 5 (or 5*, the enantiomerof 5, or mixtures thereof).

Compound 5 (or 5*, the enantiomer of 5, or mixtures thereof) prepared byany of the methods presented herein can be converted to a sulfonic saltof formula 14 (or 14*, the enantiomer of 14, or mixtures thereof), asshown in Scheme 4. This can be accomplished by a) combining compound 5(or 5*, the enantiomer of 5, or mixtures thereof), a crystallizationsolvent or crystallization solvent mixture (e.g., EtOAc, iPrOAc, EtOH,MeOH, or acetonitrile, or combinations thereof), and a sulfonic acid

(e.g., Z=Ph, p-tolyl, Me, or Et), b) diluting the mixture with anappropriate crystallization co-solvent or crystallization co-solventmixture (e.g., pentane, methyl t-butylether, hexane, heptane, ortoluene, or combinations thereof), and c) filtering the mixture toobtain a sulfonic acid salt of formula 14 (or 14*, the enantiomer of14).

The following describes the HPLC method used in assessing HPLC purity ofthe examples and intermediates presented below:

-   Column: Waters XBridge Shield RP18, 4.6×150 mm, 3.5 μm-   Mobile Phase: A=0.05% TFA/H20, B=0.05% TFA/ACN-   Autosampler flush: 1:1 ACN/H₂O-   Diluent: 1:1 ACN/H₂O-   Flow Rate: 1.0 ml/min-   Temperature: 45° C.-   Detector: UV 275 nm

Pump Parameters:

Step Segment Time A B Curve 0 0.5 80.0 20.0 0 1 15.0 60.0 40.0 1 2 10.015.0 85.0 1 3 5.0 0.0 100.0 1 4 2.0 0.0 100.0 0 5 8.0 80.0 20.0 0

Process Development—Catalyst Selection

The following table (Table 1) captures the experimental conditions, %conversion, and enantiomeric ratio of the asymmetric Henry reaction forconversion of 16-Br to 1-Br and 1*-Br using various chiral catalystsystems.

TABLE 1 e.r. Entry ligand Cu(II) CH₃NO₂ base solvent Temp/time % Conv.1-Br:1*-Br 1 — —  5 eq K₂CO₃ —  RT, 2 h   92% 50:50 (1.0 eq) 2 — — 10 eqEt₃N EtOH RT, 45 h — 50:50 (0.09 eq) 3 17 — 10 eq — THF RT, 23.5 h   >95% 90:10 (0.05 eq) 4 L2 Cu(OTf)₂ 10 eq Et₃N EtOH RT, 70 h 11.8% 52:48(0.1 eq) (0.1 eq) (0.09 eq) 5 L3 Cu(OTf)₂ 10 eq Et₃N EtOH RT, 70 h   <1%50:50 (0.1 eq) (0.1 eq) (0.09 eq) 6 L4 Cu(OTf)₂ 10 eq Et₃N EtOH RT, 16 h  24% 52:48 (0.1 eq) (0.1 eq) (0.09 eq) 7 L5 Cu(OTf)₂ 10 eq Et₃N EtOHRT, 70 h 11.6% 50:50 (0.1 eq) (0.1 eq) (0.09 eq) 8 L7 Cu(OTf)₂ 10 eqEt₃N EtOH RT, 16 h No conv. — (0.1 eq) (0.1 eq) (0.09 eq) 9 L10 Cu(OTf)₂10 eq Et₃N EtOH RT, 16 h No conv. — (0.1 eq) (0.1 eq) (0.09 eq) 10 — —10 eq Et₃N THF RT, 18 h 10.2% 50:50 (0.09 eq) 11 — Cu(OTf)₂ 10 eq Et₃NTHF RT, 18 h No conv. 50:50 (0.1 eq) (0.09 eq) 12 L2 Cu(OTf)₂ 10 eq Et₃NTHF  RT, 24 h:  4.7% 51:49 (0.1 eq) (0.1 eq) (0.09 eq) 13 L3 Cu(OTf)₂ 10eq Et₃N THF RT, 24 h  3.4% 50:50 (0.1 eq) (0.1 eq) (0.09 eq) 14 L4Cu(OTf)₂ 10 eq Et₃N THF RT, 24 h 48.7% 50:50 (0.1 eq) (0.1 eq) (0.09 eq)15 L5 Cu(OTf)₂ 10 eq Et₃N THF RT, 24 h 11.6% 50:50 (0.1 eq) (0.1 eq)(0.09 eq)

Asymmetric Henry reactions employing chiral ligands L2, L3, L4, L5, L7,and L10 resulted in little-to-no reaction conversion and with nodemonstrated stereoselectivity. In contrast, the asymmetric Henryreaction using chiral ligand 17 resulted in complete reaction conversionand high enantioselectivity (see, Entry 3 from Table 1). Without beingbound by any scientific theory, it is believed that the bicyclic natureof and high basicity of chiral ligands of Formula 3 or 3* (e.g., chiralligand 17) may account for the increased reaction conversion andenantioselectivty when compared to the monocyclic and less basic natureof chiral ligands L2, L3, L4, L5, L7, and L10.

Example 1 Preparation of ethyl2-(5-bromopyridin-2-yl)-2,2-difluoroacetate (15-Br)

In a clean multi-neck round bottom flask, copper powder (274.7 g, 2.05eq) was suspended in dimethyl sulfoxide (3.5 L, 7 vol) at 20-35° C.Ethyl bromodifluoroacetate (449 g, 1.05 eq) was slowly added to thereaction mixture at 20-25° C. and stirred for 1-2 h. 2,5-dibromopyridine(500 g, 1 eq) was added to the reaction mixture and the temperature wasincreased to 35-40° C. The reaction mixture was maintained at thistemperature for 18-24 h and the reaction progress was monitored by GC.

After the completion of the reaction, ethyl acetate (7 L, 14 vol) wasadded to the reaction mixture and stirring was continued for 60-90 minat 20-35° C. The reaction mixture was filtered through a Celite bed (100g; 0.2 times w/w Celite and 1 L; 2 vol ethyl acetate). The reactor waswashed with ethyl acetate (6 L, 12 vol) and the washings were filteredthrough a Celite bed. The Celite bed was finally washed with ethylacetate (1 L, 2 vol) and all the filtered mother liquors were combined.The pooled ethyl acetate solution was cooled to 8-10° C., washed withthe buffer solution (5 L, 10 vol) below 15° C. (Note: The addition ofbuffer solution was exothermic in nature. Controlled addition of bufferwas required to maintain the reaction mixture temperature below 15° C.).The ethyl acetate layer was washed again with the buffer solution until(7.5 L; 3×5 vol) the aqueous layer remained colorless. The organic layerwas washed with a 1:1 solution of 10% w/w aqueous sodium chloride andthe buffer solution (2.5 L; 5 vol). The organic layer was thentransferred into a dry reactor and the ethyl acetate was distilled underreduced pressure to get crude 15-Br.

The crude 15-Br was purified by high vacuum fractional distillation andthe distilled fractions having 15-Br purity greater than 93% (with thedialkylated not more than 2% and starting material less than 0.5%) werepooled together to afford 15-Br.

Yield after distillation: 47.7% with >93% purity by GC (pale yellowliquid). Another 10% yield was obtained by re-distillation of impurefractions resulting in overall yield of 55-60%.

¹H NMR: δ values with respect to TMS (DMSO-d₆; 400 MHz): 8.85 (1H, d,1.6 Hz), 8.34 (1H, dd, J=2.0 Hz, 6.8 Hz), 7.83 (1H, d, J=6.8 Hz), 4.33(2H, q, J=6.0 Hz), 1.22 (3H, t, J=6.0 Hz). ¹³C NMR: 162.22 (t, —C═O),150.40 (Ar—C—), 149.35 (t, Ar—C), 140.52 (Ar—C), 123.01 (Ar—C), 122.07(Ar—C), 111.80 (t, —CF₂), 63.23 (—OCH₂—), 13.45 (—CH₂CH₃).

Example 2 Preparation of2-(5-bromopyridin-2-yl)-1-(2,4-difluorophenyl)-2,2-difluoroethanone(16-Br) A. One-Step Method

1-Bromo-2,4-difluorobenzene (268.7 g; 1.3 eq) was dissolved in methyltert butyl ether (MTBE, 3.78 L, 12.6 vol) at 20-35° C. and the reactionmixture was cooled to −70 to −65° C. using an acetone/dry ice bath.n-Butyl lithium (689 mL, 1.3 eq; 2.5 M) was then added to the reactionmixture maintaining the reaction temperature below −65° C. (Note:Controlled addition of the n-Butyl Lithium to the reaction mixture wasneeded to maintain the reaction mixture temperature below −65° C.).After maintaining the reaction mixture at this temperature for 30-45min, 15-Br (300 g, 1 eq) dissolved in MTBE (900 mL, 3 vol) was added tothe reaction mixture below −65° C. The reaction mixture was continued tostir at this temperature for 60-90 min and the reaction progress wasmonitored by GC.

The reaction was quenched by slow addition of a 20% w/w ammoniumchloride solution (750 mL, 2.5 vol) below −65° C. The reaction mixturewas gradually warmed to 20-35° C. and an additional amount of a 20% w/wammonium chloride solution (750 mL, 2.5 vol) was added. The aqueouslayer was separated, the organic layer was washed with a 10% w/w sodiumbicarbonate solution (600 mL, 2 vol) followed by a 5% sodium chloridewash (600 mL, 2 vol). The organic layer was dried over sodium sulfate(60 g; 0.2 times w/w), filtered and the sodium sulfate was washed withMTBE (300 mL, 1 vol). The organic layer along with washings wasdistilled below 45° C. under reduced pressure until no more solvent wascollected in the receiver. The distillation temperature was increased to55-60° C., maintained under vacuum for 3-4 h and cooled to 20-35° C. toafford 275 g (73.6% yield, 72.71% purity by HPLC) of 16-Br as a paleyellow liquid.

¹H NMR: δ values with respect to TMS (DMSO-d₆; 400 MHz):8.63 (1H, d, 1.6Hz, Ar—H), 8.07-8.01 (2H, m, 2×Ar—H), 7.72 (1H, d, J=6.8 Hz, Ar—H),7.07-6.82 (1H, m, Ar—H), 6.81-6.80 (1H, m, Ar—H).

¹³C NMR: 185.60 (t, —C═O), 166.42 (dd, Ar—C—), 162.24 (dd, Ar—C), 150.80(Ar—C), 150.35 (Ar—C), 140.02 (Ar—C), 133.82 (Ar—C), 123.06 (Ar—C),1122.33 (Ar—C), 118.44 (Ar—C), 114.07 (—CF₂—), 122.07 (Ar—C), 105.09(Ar—C).

B. Two-Step Method Via 15b-Br

15-Br (147.0 g) was dissolved in n-heptane (1.21 L) and transferred to a5-L reactor equipped with overhead stirrer, thermocouple, condenser andaddition funnel. Morpholine (202 ml) was added. The solution was heatedto 60° C. and stirred overnight. The reaction was complete by HPLCanalysis (0.2% 15-Br; 94.7% 15b-Br). The reaction was cooled to roomtemperature and 1.21 L of MTBE was added. The solution was cooled to ˜4°C. and quenched by slow addition of 30% citric acid (563 ml) to maintainthe internal temperature <15° C. After stirring for one hour the layerswere allowed to settle and were separated (Aq. pH=5). The organic layerwas washed with 30% citric acid (322 ml) and 9% NaHCO₃ (322 ml, aq. pH730 after separation). The organic layer was concentrated on the rotaryevaporator to 454 g (some precipitation started immediately andincreased during concentration). After stirring at room temperature thesuspension was filtered and the product cake was washed with n-heptane(200 ml). The solid was dried in a vacuum oven at room temperature toprovide 129.2 g (77%) dense powder. The purity was 96.5% by HPLCanalysis.

To a 1-L flask equipped with overhead stirring, thermocouple, condenserand addition funnel was added magnesium turnings (14.65 g), THF (580 ml)and 1-bromo-2,4-difluorobenzene (30.2 g, 0.39 equiv). The mixture wasstirred until the reaction initiated and self-heating brought thereaction temperature to 44° C. The temperature was controlled with acooling bath as the remaining 1-bromo-2,4-difluorobenzene (86.1 g, 1.11equiv) was added over about 30 min. at an internal temperature of 35-40°C. The reaction was stirred for 2 hours while gradually cooling to roomtemperature. The dark yellow solution was further cooled to 12° C.

During the Grignard formation, a jacketed 2-L flask equipped withoverhead stirring, thermocouple, and addition funnel was charged withmorpholine amide 15b-Br (129.0 g) and THF (645 ml). The mixture wasstirred at room temperature until the solid dissolved, and then thesolution was cooled to −8.7° C. The Grignard solution was added viaaddition funnel over about 30 min. at a temperature of −5 to 0° C. Thereaction was stirred at 0° C. for 1 hour and endpointed by HPLCanalysis. The reaction mixture was cooled to −5° C. and quenched by slowaddition of 2N HCl over 1 hour at ≤10° C. The mixture was stirred for0.5 h then the layers were allowed to settle and were separated. Theaqueous layer was extracted with MTBE (280 ml). The combined organiclayers were washed with 9% NaHCO₃ (263 g) and 20% NaCl (258 ml). Theorganic layer was concentrated on the rotary evaporator with THF rinsesto transfer all the solution to the distillation flask. Additional THF(100 ml) and toluene (3×100 ml) were added and distilled to removeresidual water from the product. After drying under vacuum, the residuewas 159.8 g of a dark brown waxy solid (>theory). The purity wasapproximately 93% by HPLC analysis.

Grignard Formation/Coupling Reaction 2:

Magnesium (0.022 kg, 0.903 mol), 1-bromo-2,4-difluorobenzene (0.027 kg,0.14 mol) and tetrahydrofuran (THF) (1.4 L) were charged to a 2 Lreactor fitted with a nitrogen inlet/outlet, 0.25 L dropping funnel,temperature probe and reflux condenser. After stirring for ca. 40 min at22° C., the reaction initiated and was allowed to reach 35° C. Coolingwas applied and further 1-bromo-2,4-difluorobenzene (0.153 kg, 0.79 mol)was added at 35-40° C. over 0.5 hr. On completion of the addition, thereaction was stirred at 35-40° C. for a further 1 h before coolingsolution of the Grignard reagent to 20-25° C. over 1 hr. During the 1 hrcooling period, 15b-Br (0.2 kg, 0.62 mol) and THF (0.8 L) were chargedto a 5 L reactor fitted with a nitrogen inlet/outlet, 0.5 L droppingfunnel, temperature probe and reflux condenser and stirred at 15-20° C.to give a solution before cooling to −5 to 0° C.

The Grignard reagent was added to the solution of morpholine amide inTHF at −3 to 2° C. over 50 min and the solution stirred at approximately0° C. for 1 hr. A sample of the reaction mixture was submitted for GCanalysis. A 1 ml sample was quenched into 2 M hydrochloric acid solution(5 ml) and extracted with MTBE (2 ml). The organic layer was submittedfor analysis, which indicated 0.76% morpholine amide remaining.

The reaction was quenched by the addition of a 2 M hydrochloric acidsolution (1 L) over 0.75 hr at less than 10° C. and stirred for afurther 0.5 hr. Stirring was stopped and the phases allowed to separate.The lower aqueous layer was removed and extracted with tert-butylmethylether (MTBE) (0.4 L). The combined organic layers were washed with asaturated sodium hydrogen carbonate solution (0.4 L) and a saturatedsodium chloride solution (0.4 L). The solvent was evaporated undervacuum at less than 50° C. and co-distilled with portions of toluene(0.2 L) until the water content by Karl Fischer (KF) analysis was lessthan 0.1%.

Toluene (0.37 L) and n-heptane (0.37 L) were added to the residuetogether with SilicaFlash P60 (40-63 micron) (0.11 kg), and the reactionstirred at 20-25° C. for 1 hr. The reaction was filtered and washed withtoluene/n-heptane (1:1) (2 L). The solvent was evaporated at <50° C. andsolvent swapped into THF to give an approximately 36 wt % solution of16-Br. Gravimetric analysis of a sample of the toluene/n-heptanesolution prior to evaporation indicated a mass yield of 0.21 kg (98.5%).GC assay of this material was 95.34%, to give a contained yield of93.9%. GC (AUC) analysis of an evaporated sample was 94.5%, and HPLC(AUC) was 97.1%.

Example 3 Preparation of1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitropropan-2-ol(1-Br or 1*-Br)

A reaction flask was charged with 16-Br (1.3 g, 3.7 mmol, 1.0 eq) andTHF (3.3 mL) yielding a yellow solution. The organocatalyst 17 (59 mg,0.19 mmol, 0.05 eq), prepared according to J. Am. Chem. Soc. 2012, 164,169-172, was added to the mixture and the contents were cooled to 5° C.Subsequently, nitromethane (2.0 mL, 2.27 g, 37 mmol 10 eq) was added andthe mixture was stirred at 5° C. for 23.5 h. At this point, an HPLCsample was taken to determine conversion (>95% conversion) andenantiomeric ratio (ca. 90:10 1-Br:1*-Br). For the work up, the mixturewas diluted with ethyl acetate (12 mL) and an aqueous solution of aceticacid (acetic acid 0.6 ml and water 10 ml) was added. The phases wereseparated and the organic phase was washed with water (8 mL) and brine(8 mL). The volatiles were removed under reduced pressure to obtain 1.15g (75% yield) of the crude product.

¹H NMR: δ values with respect to TMS (DMSO-d₆; 400 MHz): 8.59 (1H, d,J=2.0 Hz), 7.92 (1H, dd, J=8.4 Hz, 2.3 Hz), 7.45 (1H, m), 7.34 (1H, dd,J=8.4 Hz, 2.3 Hz), 6.86-6.75 (2H, m), 5.70 (1H, d, J=12.8 Hz), 5.16 (1H,d, J=12.8 Hz).

Chiral HPLC: Retention Times: 10.97 min (1*-Br); 14.82 min (1-Br)

HPLC Set up HPLC column Chiralpack AD 250 mm × 4.6 mm × 5 μm Columntemperature 25° C. Sample temperature 25° C. Flow rate 0.8 mL/minInjection Volume 3 μL Wavelength 254 Run time 20 min Mobile Phase AHexane Mobile Phase B n-Propanol

Example 4 Preparation of3-amino-1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoropropan-2-ol(11-Br or 11*-Br)

A chamber of a screening autoclave was charged with 1-Br/1*-Br (150 mg,0.366 mmol), Noblyst® P8071¹ (ca. 0.40 mol % Pt relative to 1-Br/1*-Br)and MeOH (1.5 mL). The chamber was flushed several times with H₂ andpressurized to 4 bar. After 16 h, a sample was analyzed by HPLC. Uponreaction completion, the reaction mixture was filtered through a glassfilter and the solvent was removed under reduced pressure to obtain thecrude product.

¹H NMR: δ values with respect to TMS (CDCl₃; 400 MHz): 8.59 (1H, d,J=2.1 Hz), 7.83 (1H, dd, J=8.4 Hz, 2.2 Hz), 7.43 (1H, m), 7.24 (1H, d,J=8.4 Hz), 6.80-6.67 (2H, m), 5.20 (2H, s), 3.89 (1H, d, J=14.2 Hz),3.47 (1H, d, J=14.2 Hz).

Achiral HPLC: Retention Times: 7.25 min (11-Br/11*-Br)

HPLC Set up HPLC column Agilent Bonus RP 75 mm × 4.6 mm 1.8 μm Columntemperature 25° C. Sample temperature 25° C. Flow rate 0.8 mL/minInjection Volume 3 μL Wavelength 254 Run time 18 min Mobile Phase AWater + 0.1% TFA Mobile Phase B ACN + 0.1% TFA

Enantioenrichment of 11-Br/11*-Br

Di-p-toluoyl-L-tartaric acid (0.069 kg, 0.178 ml; 0.3 eq.) was chargedunder nitrogen to a 5 L reactor equipped with a nitrogen inlet/outlet. Asolution of 11-Br/11*-Br in isopropyl alcohol (IPA,1.718 kg; containedmass 0.225 kg, 0.59 mol; 1 eq.) was added, followed by acetonitrile(0.35 kg). The reaction mixture was stirred at approximately 20° C. anda solution resulted. The reaction was heated to 50-55° C. (target 52°C.) and stirred at this temperature for 4 hr, during which time aprecipitate resulted. An in-process chiral HPLC sample of the reactionwas taken by hot filtration of the sample and washing withIPA/acetonitrile (4:1). This indicated a chiral purity of >99%.

The reaction was allowed to cool and stir at 20-25° C. over 16 hr. Asecond sample was submitted for chiral HPLC analysis, which was 99.5%.The reaction mixture was filtered and washed with a mixture ofIPA/acetonitrile (4:1) (0.84 L). The resulting solid was dried undervacuum at 50° C. to give 11-Br hemi L-DTTA salt (0.113 kg) as a whitesolid. The mass yield was 33.2%, which is 66.35% of the desired isomer.Chiral HPLC was 99.6%, and achiral HPLC was 99.7%.

Example 5 Preparation of1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol(13-Br or 13*-Br)

11-Br/11*-Br (20.0 g, 1 eq.) was added to acetic acid (50 mL, 2.5 vol)at 25-35° C. followed by the addition of anhydrous sodium acetate (4.32g, 1 eq) and trimethyl orthoformate (15.08 g, 2.7 eq). The reactionmixture was stirred for 15-20 min at this temperature and trimethylsilylazide (12.74 g, 2.1 eq) was added to the reaction mixture (Chilled waterwas circulated through the condenser to minimize the loss oftrimethylsilyl azide from the reaction mixture by evaporation). Thereaction mixture was then heated to 70-75° C. and maintained at thistemperature for 2-3 h. The reaction progress was monitored by HPLC. Oncethe reaction was complete, the reaction mixture was cooled to 25-35° C.and water (200 mL, 10 vol) was added. The reaction mixture was extractedwith ethyl acetate (400 mL, 20 vol) and the aqueous layer was backextracted with ethyl acetate (100 mL, 5 vol). The combined organiclayers were washed with 10% potassium carbonate solution (3×200 mL; 3×10vol) followed by a 10% NaCl wash (1×200 mL, 10 vol). The organic layerwas distilled under reduced pressure below 45° C. The crude obtained wasazeotroped with heptanes (3×200 mL) to get 21.5 g (94% yield, 99.26 5purity) of the tetrazole 13-Br/13*-Br compound as pale brown solid (lowmelting solid).

¹H NMR: δ values with respect to TMS (DMSO-d₆; 400 MHz NMRinstrument):9.13 (1H, Ar—H), 8.74 (1H, Ar—H), 8.22-8.20 (1H, m, Ar—H),7.44 (1H, d, J=7.2 Hz, Ar—H), 7.29 (1H, Ar—H), 7.23-7.17 (1H, m, Ar—H),6.92-6.88 (1H, Ar—H), 5.61 (1H, d,J=11.2 Hz, —OCH_(A)H_(B)—), 5.08 (1H,d, J=5.6 Hz, —OCH_(A)H_(B)—).

¹³C NMR: 163.67-161.59 (dd, Ar—C—), 160.60-158.50 (dd, Ar—C—), 149.65(Ar—C), 144.99 (Ar—C), 139.75 (Ar—C), 131.65 (Ar—C), 124.26 (Ar—C),122.32 (d, Ar—C), 119.16 (t, —CF₂—), 118.70 (d, Ar—C), 111.05 (d, Ar—C)104.29 (t, Ar—C), 76.79 (t, —C—OH), 59.72 (Ar—C), 50.23 (—OCH₂N—).

Example 6 Preparation of2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol(5-OCH₂CF₃ or 5*-OCH₂CF₃)

A. Preparation of 5-OCH₂CF₃ or 5*-OCH₂CF₃ via 13-Br or 13*-Br

Synthesis of4,4,5,5-tetramethyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)-1,3,2-dioxaborolane

Potassium carbonate (59.7 g, 2.2 eq.) was added to a slurry of DMF (190mL, 3.8 Vol.), 4-Bromo phenol (37.4 g, 1.1 eq.) and 2,2,2-trifluroethyltosylate (50.0 g, 1.0 eq.) at 20-35° C. under an inert atmosphere. Thereaction mixture was heated to 115-120° C. and maintained at thistemperature for 15-18 h. The reaction progress was monitored by GC. Thereaction mixture was then cooled to 20-35° C., toluene (200 mL, 4.0vol.) and water (365 mL, 7.3 vol.) were added at the same temperature,stirred for 10-15 minutes and separated the layers. The aqueous layerwas extracted with toluene (200 mL, 4.0 vol.). The organic layers werecombined and washed with a 2M sodium hydroxide solution (175 mL, 3.5vol.) followed by a 20% sodium chloride solution (175 mL, 3.5 vol.). Theorganic layer was then dried over anhydrous sodium sulfate and filtered.The toluene layer was transferred into a clean reactor, spurged withargon gas for not less than 1 h. Bis(Pinacolato) diborane (47 g, 1.1eq.), potassium acetate (49.6 g, 3.0 eq.) and 1,4-dioxane (430 mL, 10vol.) were added at 20-35° C., and the reaction mixture was spurged withargon gas for at least 1 h. Pd(dppf)Cl₂ (6.88 g, 0.05 eq) was added tothe reaction mixture and continued the argon spurging for 10-15 minutes.The reaction mixture temperature was increased to 70-75° C., maintainedthe temperature under argon atmosphere for 15-35 h and monitored thereaction progress by GC. The reaction mixture was cooled to 20-35° C.,filtered the reaction mixture through a Celite pad, and washed withethyl acetate (86 mL, 2 vol.). The filtrate was washed with water (430mL, 10 vol.). The aqueous layer was extracted with ethyl acetate (258mL, 6 vol.) and washed the combined organic layers with a 10% sodiumchloride solution (215 mL, 5 vol.). The organic layer was dried overanhydrous sodium sulfate (43 g, 1 time w/w), filtered and concentratedunder reduced pressure below 45° C. to afford crude4,4,5,5-tetramethyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)-1,3,2-dioxaborolane(65 g; 71% yield with the purity of 85.18% by GC). The crude4,4,5,5-tetramethyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)-1,3,2-dioxaborolane(65 g, 1 eq.) was dissolved in 10% ethyl acetate—n-Heptane (455 mL, 7vol.) and stirred for 30-50 minutes at 20-35° C. The solution wasfiltered through a Celite bed and washed with 10% ethyl acetate inn-Heptane (195 mL, 3 vol.). The filtrate and washings were pooledtogether, concentrated under vacuum below 45° C. to afford4,4,5,5-tetramethyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)-1,3,2-dioxaborolaneas a thick syrup (45.5 g; 70% recovery). This was then dissolved in 3%ethyl acetate-n-heptane (4 vol.) and adsorbed on 100-200 M silica gel (2times), eluted through silica (4 times) using 3% ethylacetate—n-heptane. The product rich fractions were pooled together andconcentrated under vacuum. The column purified fractions (>85% pure)were transferred into a round bottom flask equipped with a distillationset-up. The compound was distilled under high vacuum below 180° C. andcollected into multiple fractions. The purity of fractions was analyzedby GC (should be >98% with single max impurity <1.0%). The less purefractions (>85% and <98% pure fraction) were pooled together and thedistillation was repeated to get 19 g (32% yield) of4,4,5,5-tetramethyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)-1,3,2-dioxaborolaneas a pale yellow liquid.

¹H NMR: δ values with respect to TMS (DMSO-d⁶; 400 MHz):7.64 (2H, d, 6.8Hz), 7.06 (2H, d, J=6.4 Hz), 4.79 (2H, q, J=6.8 Hz), 1.28 (12H, s).

¹³C NMR: 159.46 (Ar—C—O—), 136.24 (2×Ar—C—), 127.77-120.9 (q, —CF₃),122.0 (Ar—C—B), 114.22 (2×Ar—C—), 64.75 (q, J=27.5 Hz).

Synthesis of2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol(5-OCH₂CF₃ or 5*-OCH₂CF₃)

13-Br/13*-Br (14 g, 0.03 mol, 1 eq) was added to tetrahydrofuran (168mL, 12 vol) at 25-35° C. and the resulting solution was heated to 40-45°C. The reaction mixture was maintained at this temperature for 20-30 minunder argon bubbling. Sodium carbonate (8.59 g, 0.08 mol, 2.5 eq) andwater (21 mL, 1.5 vol) were added into the reaction mixture and thebubbling of argon was continued for another 20-30 min.4,4,5,5-tetramethyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)-1,3,2-dioxaborolane(10.76 g, 1.1 eq) dissolved in tetrahydrofuran (42 mL, 3 vol) was addedinto the reaction mixture and argon bubbling was continued for 20-30min. Pd(dppf)Cl₂ (2.65 g, 0.1 eq) was added to the reaction mixtureunder argon bubbling and stirred for 20-30 min (Reaction mixture turnedinto dark red color). The reaction mixture was heated to 65-70° C. andmaintained at this temperature for 3-4 h. The reaction progress wasmonitored by HPLC. The reaction mixture was cooled to 40-45° C. and thesolvent was distilled under reduced pressure. Toluene (350 mL, 25 vol.)was added to the reaction mixture and stirred for 10-15 min followed bythe addition of water (140 mL, 10 vol). The reaction mixture wasfiltered through Hyflo (42 g, 3 times), the layers were separated andthe organic layer was washed with water (70 mL, 5 vol) and a 20% w/wsodium chloride solution (140 mL, 10 vol). The organic layer was treatedwith charcoal (5.6 g, 0.4 times, neutral charcoal), filtered throughHyflo. (1S)-10-Camphor sulfonic acid (7.2 g, 1 eq.) was added to thetoluene layer and the resulting mixture was heated to 70-75° C. for 2-3h. The reaction mixture was gradually cooled to 25-35° C. and stirredfor 1-2 h. The solids were filtered, washed with toluene (2×5 vol.) andthen dried under vacuum below 45° C. to afford 18.0 g of an off whitesolid. The solids (13.5 g, 1 eq.) were suspended in toluene (135 mL, 10vol) and neutralized by adding 1M NaOH solution (1.48 vol, 1.1 eq) at25-35° C. and stirred for 20-30 min. Water (67.5 mL, 5 vol) was added tothe reaction mixture and stirred for 10-15 min, and then the layers wereseparated. The organic layer was washed with water (67.5 mL, 5 vol) toremove the traces of CSA. The toluene was removed under reduced pressurebelow 45° C. to afford crude 5-OCH₂CF₃ or 5*-OCH₂CF₃. Traces of toluenewere removed by azeotroping with ethanol (3×10 vol), after which lightbrown solid of crude 5-OCH₂CF₃ or 5*-OCH₂CF₃ (7.5 g, 80% yield) wasobtained.

The crude 5-OCH₂CF₃ or 5*-OCH₂CF₃ (5 g) was dissolved in ethanol (90 mL,18 vol.) at 20-35° C. and heated to 40-45° C. Water (14 vol) was addedto the solution at 40-45° C., the solution was maintained at thistemperature for 30-45 min and then gradually cooled to 20-35° C. Theresulting suspension was continued to stir for 16-18 h at 20-35° C., anadditional amount of water (4 vol.) was added and the stirring continuedfor 3-4 h. The solids were filtered to afford 4.0 g (80% recovery) of5-OCH₂CF₃ or 5*-OCH₂CF₃ (HPLC purity >98%) as an off-white solid.

¹H NMR: δ values with respect to TMS (DMSO-d₆; 400 MHz):9.15 (1H, s,Ar—H), 8.93 (1H, d, J=0.8 Hz, Ar—H), 8.22-8.20 (1H, m, Ar—H), 7.80 (2H,d, J=6.8 Hz, Ar—H), 7.52 (1H, d, J=6.8 Hz, Ar—H), 7.29 (1H, d, J=3.2 Hz,Ar—H), 7.27-7.21 (1H, m, Ar—H), 7.23-7.21 (2H, d, J=6.8 Hz, Ar—H), 7.19(1H, d, J=6.8 Hz, Ar—H), 6.93-6.89 (1H, m, Ar—H), 5.68 (1H, J=12 Hz,—CH_(A)H_(B)), 5.12 (2H, d, J=11.6 Hz, —CH_(A)H_(B)), 4.85 (2H, q, J=7.6Hz).

¹³C NMR: 163.93-158.33 (m, 2×Ar—C), 157.56 (Ar—C), 149.32 (t, Ar—C),146.40 (Ar—C), 145.02 (Ar—C), 136.20 (Ar—C), 134.26 (2×Ar—C),131.88-131.74 (m, AR—C), 129.72 (Ar—C), 128.47 (2×Ar—C), 123.97 (q,—CF₂—), 122.41 (Ar—C), 119.30 (—CF₃), 118.99 (Ar—C), 115.65 (2×Ar—C),110.99 (d, Ar—C), 104.22 (t, Ar—C), 77.41-76.80 (m, Ar—C), 64.72 (q,—OCH₂—CF₃), 50.54 (—CH₂—N—).

B. Preparation of 5-OCH₂CF₃ or 5*-OCH₂CF₃ via 11-Br or 11*-Br

Synthesis of3-amino-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol(4-OCH₂CF₃ or 4*-OCH₂CF₃)

Potassium carbonate (30.4 g) and water (53.3 g) were charged to a 1-Lflask equipped with overhead stirring, thermocouple, and nitrogen/vacuuminlet valve, and stirred until dissolved. The boronic acid (19.37 g), asolution of 11-Br or 11*-Br in 2-butanol (103.5 g, 27.8 g theoretical11-Br or 11*-Br)) and 2-BuOH (147.1 g) were added and stirred to form aclear mixture. The flask was evacuated and refilled with nitrogen 3times. Pd(dppf)₂Cl₂ (0.30 g) was added and stirred to form a lightorange solution. The flask was evacuated and refilled with nitrogen 4times. The mixture was heated to 85° C. and stirred overnight andendpointed by HPLC analysis. The reaction mixture was cooled to 60° C.and the layers were allowed to settle. The aqueous layer was separated.The organic layer was washed with a 5% NaCl solution (5×100 ml) at30-40° C. The organic layer was filtered and transferred to a cleanflask with rinses of 2-BuOH. The combined solution was 309.7 g, watercontent 13.6 wt % by KF analysis. The solution was diluted with 2-BuOH(189 g) and water (10 g). Theoretically the solution contained 34.8 gproduct, 522 ml (15 volumes) of 2-BuOH, and 52.2 ml (1.5 volumes) ofwater.

Synthesis of2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol(5-OCH₂CF₃ or 5*-OCH₂CF₃)

L-Tartaric acid (13.25 g) was added to the above mixture and the mixturewas heated to a target temperature of 70-75° C. During the heat-up, athick suspension formed. After about 15 minutes at 70-72° C. thesuspension became fluid and easily stirred. The suspension was cooled ata rate of 10° C./hour to 25° C. then stirred at 25° C. for about 10hours. The product was collected on a vacuum filter and washed with 10:1(v/v) 2-BuOH/water (50 ml) and 2-butanol (40 ml). The salt was dried ina vacuum oven at 60° C. with a nitrogen purge for 2 days. The yield was40.08 g of the titled compound as a fluffy, grayish-white solid. Thewater content was 0.13 wt % by KF analysis. The yield was 87.3% with anHPLC purity of 99.48%.

To a 350 ml pressure bottle were charged acetic acid (73 ml), the aboveproduct (34.8 g), sodium acetate (4.58 g) and trimethylorthoformate(16.0 g). The mixture was stirred for 18 min. at room temperature untila uniform suspension was obtained. Azidotrimethylsilane (8.88 g) wasadded and the bottle was sealed. The bottle was immersed in an oil bathand magnetically stirred. The oil bath was at 52° C. initially, and waswarmed to 62-64° C. over about ½ hour. The suspension was stirred at62-64° C. overnight. After 20.5 hours the suspension was cooled to roomtemperature and sampled. The reaction was complete by HPLC analysis. Thereaction was combined with three other reactions that used the same rawmaterial lots and general procedure (total of 3.0 g additional startingmaterial). The combined reactions were diluted with ethyl acetate (370ml) and water (368 ml) and stirred for about ½ hour at room temperature.The layers were settled and separated. The organic layer was washed witha 10% K₂CO₃ solution (370 ml/397 g) and a 20% NaCl solution (370 ml/424g). The organic layer (319 g) was concentrated, diluted with ethanol(202 g), filtered, and rinsed with ethanol (83 g). The combined filtratewas concentrated to 74 g of an amber solution.

The crude 5-OCH₂CF₃ or 5*-OCH₂CF₃ solution in ethanol (74 g solution,containing theoretically 31.9 g 5-OCH₂CF₃ or 5*-OCH₂CF₃) was transferredto a 2-L flask equipped with overhead stirring, thermocouple, andaddition funnel. Ethanol (335 g) was added including that used tocomplete the transfer of the 5-OCH₂CF₃ or 5*-OCH₂CF₃ solution. Thesolution was heated to nominally 50° C. and water (392 g) was added over12 minutes. The resulting hazy solution was seeded with 5-OCH₂CF₃ or5*-OCH₂CF₃ crystals and stirred at 50° C. After about ½ hour the mixturewas allowed to cool to 40° C. over about ½ hour during which timecrystallization started. Some darker colored chunky solid separated outfrom the main suspension. The pH of the crystallizing mixture wasadjusted from 4.5 to 6 using 41% KOH (1.7 g). After about 1 hour a goodsuspension had formed. Additional water (191 g) was added slowly over ½hour. The suspension was heated to 50° C. and cooled at 5° C./min toroom temperature. After stirring overnight the suspension was cooled ina water bath to 16° C. and filtered after 1 hour. The wet cake waswashed with 55:45 (v/v) water/ethanol (2×50 ml) and air-dried on thevacuum filter funnel overnight. Further drying at 40° C. in a vacuumoven with a nitrogen bleed resulted in no additional weight loss. Theyield was 30.2 g of off-white fine powder plus some darker granularmaterial. By in-process HPLC analysis there was no difference in thechemical purity of the darker and lighter materials. The purity was99.4%. The water content was 2.16 wt % by KF analysis. The residualethanol was 1.7 wt % estimated by ¹H NMR analysis. The corrected yieldwas 29.0 g, 91.0% overall yield for tetrazole formation andcrystallization. The melting point was 65° C. by DSC analysis.

C. Alternate Preparation of 5-OCH₂CF₃ via 11-Br

A 5 L reactor equipped with a nitrogen inlet/outlet was charged undernitrogen with 11-Br hemi di-p-toluoyl-L-tartaric acid salt (0.145 kg,0.253 mol) and MTBE (0.725 L). The suspension was stirred and a solutionof potassium carbonate (0.105 kg, 0.759 mol; 3 eq.) in water (0.945 kg)added. The reaction was stirred for 0.25 hr during which time a solutionresulted. Stirring was stopped and the phases were allowed to separate.The lower aqueous layer (pH 10) was removed and extracted with MTBE(0.725 L). The combined organic layers were evaporated under vacuum at<50° C. to give an oil (0.105 kg). 2-Butanol (0.276 kg) was added anddistilled to remove residual MTBE. 2-Butanol (0.39 kg) was added. Theweight of the 11-Br (−) solution (0.502 kg) was assumed to containtheoretical free base (0.096 kg) and 2-butanol (0.406 kg).

A solution of potassium carbonate (0.104 kg, 0.759 mol; 3 eq.) in water(0.184 kg) was prepared and charged to the reactor together with4-(trifluoroethoxy)phenyl boronic acid (0.067 kg. 0.304 mol; 1.2 eq.)The 11-Br (−) solution in 2-butanol was added, followed by a furthercharge of 2-butanol (0.364 kg). The clear solution was sparged withnitrogen for 0.5 hr before adding the Pd(dppf)Cl2 catalyst (1.03 g, 0.5mol %) and continuing the nitrogen sparge for a further 0.5 hr. Thereaction was heated to 85° C. and maintained for 18 hr, after which timethe HPLC IPC analysis indicated consumption of the starting material.

The reaction mixture was cooled to 60° C. and the lower aqueous phaseseparated (salts precipitate at low temperatures). The organic phase waswashed with a 5% sodium chloride solution (5×0.334 kg) at 30-40° C.,with a small interface layer removed with the final aqueous wash. Theorganic phase was filtered through a glass fibre filter and washedthrough with 2-butanol (0.065 L). The total solution weight (0.921 kg)was 15.7% by KF analysis (0.145 kg contained), with assumed theoreticalSuzuki free base 4-OCH₂CF₃ (0.120 kg) and 2-butanol (0.656 kg). Further2-butanol (0.793 kg) and water (0.036 kg) were added. The theoreticalreaction composition was 0.120 kg of product, 15 volumes of 2-butanoland 1.5 volumes of water.

L-Tartaric acid (0.046 kg, 0.304 mol; 1.2 eq.) was added and thereaction was heated to 70-75° C. During the heating period thesuspension thickened, but thinned out when at temperature. Heating wasmaintained for 1 hr before being cooled to 20-25° C. at approximately10° C./h and stirred for approximately 16 hr. The product was isolatedby filtration and washed with 10:1 (v/v) 2-butanol/water (0.17 L) and2-butanol (0.14 L). The solid was dried under vacuum at 60° C. to givethe tartrate salt (0.132 kg, 83%) as an off-white/grey solid. The watercontent was 2.75% by KF analysis, and HPLC was 99.5%.

A 1 L reactor equipped with condenser, temperature probe and a nitrogeninlet/outlet was charged under nitrogen with the above tartrate salt(0.13 kg, 0.208 mol), sodium acetate (0.017 kg, 0.208 mol) and aceticacid (0.273 L). Trimethyl orthoformate (0.132 kg, 1.248 mol; 6 eq.) wasadded and the suspension stirred at 20-25° C. for 1.25 hr.Azidotrimethylsilane (0.033 kg, 0.287 mol; 1.4 eq.) was added and thesuspension heated to 60-65° C. and maintained at this temperature for 16hr. A sample submitted for HPLC IPC analysis indicated 0.2% of thestarting material and 2.9% of the formamide impurity.

The reaction mixture was cooled to 20-25° C. and charged to a 5 Lreactor with ethyl acetate (1.38 L) and purified water (1.38 L). The twophase solution was stirred for 0.5 h and the aqueous phase (pH 4-5) wasremoved. A small interphase layer was retained with the organics. Theorganic phase was washed with a 10% aqueous potassium carbonate solution(2.2 kg) and separated (aqueous pH 9.3). The organic phase was washedwith a 20% sodium chloride solution (1.625 kg) and a small interphaselayer was removed with the aqueous layer.

The organic phase was charged to a 2 L reactor under nitrogen withSiliaMetS Thiol palladium scavenger (9.2 g). The reaction heated to50-55° C. and maintained at this temperature for 16 hr before beingcooled to 20-25° C. The scavenger was removed by filtration through a0.7 micron filter and washed with ethyl acetate, and the filtrate/washevaporated under vacuum at <50° C. to 100 mL. Ethanol (100%, 755 g) wasadded and the solution further evaporated to 377 g (ca. 440 mL). Thesolution (theoretical composition 109 g 5-OCH₂CF₃ and 267 g ethanol) wasdiluted with further ethanol (1.031 kg) and transferred to a 5 Lreactor). The solution was heated to 50° C. and purified water (1.34 kg)was added at 45-50° C. over 0.25 hr to give a hazy solution. This wasstirred for 0.5 hr and adjusted to pH 6 with a 40% potassium carbonatesolution (one drop). Stirring was continued for a further 1 hr at 40-42°C. and a second addition of purified water (0.65 kg) added at thistemperature over 0.5 hr. The temperature was increased to 50° C. andmaintained for 0.5 hr before cooling at 10° C./hr to 20° C. The solidwas isolated by filtration and washed with ethanol/water (45:55) (2×0.17L) and dried under vacuum at 45-50° C. to give 5-OCH₂CF₃ X-hydrate(0.0937 kg, 85.3%) as an off-white solid. HPLC (AUC) analysis was99.62%, with 0.27% formamide and 0.11% RRT 0.98.

D. Preparation of 5-OCF₃ or 5*-OCF₃

Amino-alcohols 4-OCF₃ and 4*-OCF₃ (7.0 g, 15 mmoles) were dissolved in amixture of acetonitrile (84 mL) and methanol (21 mL).(D)-Di-paratoluoyltartaric acid ((D)-DPTTA (5.89 g, 15 mmoles)) wasadded, and the reaction was warmed to 50° C. and held for 2.5 h. Theheat was then removed and the suspension was allowed to cool and stir at20-25° C. for 65 h. The suspension was cooled in an ice bath and stirredfor an additional 2 h. Solid was isolated by vacuum filtration, and thecake was washed with cold 8:2 ACN/MeOH (35 mL). After drying at 50° C.,5.18 g of 4-OCF₃/DPPTA salt was isolated, HPLC purity=99.0, ee=74.

The 4-OCF₃/DPPTA salt (5.18 g) was combined with 8:2 ACN/MeOH (68 mL)and the suspension was heated to 50° C. and held for 20 min. Aftercooling to 20-25° C., the mixture was stirred for 16 h. Solids wereisolated by vacuum filtration, and the cake washed with cold 8:2ACN/MeOH (30 mL), and pulled dry on the funnel. 2.82 g of 4-OCF₃/DPPTAsalt was obtained, 44.4% yield (from mixture of 4-OCF₃ and 4*-OCF₃),ee=97.5. The resulting solids were freebased to provide 4-OCF₃ with thesame achiral and chiral purity as the DPPTA salt.

The procedure used to generate compound 5-OCF₃ or 5*-OCF₃ is asdescribed in U.S. Pat. No. 4,426,531, Table 12.

Example 7 Preparation of2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)propan-2-olbenzenesulfonate (18-OCF₃ or 18*-OCF₃)

46.6 g of compound 5-OCF₃ or 5*-OCF₃ was dissolved in ethylacetate (360ml). The solution was filtered through a glass microfiber filter andplaced in a 2 L reaction flask equipped with an overhead stirrer,condenser, and a J-Kem thermocouple. Pharma-grade benzenesulfonic acid(BSA, 14.39 g, 1 eq) was dissolved in ethyl acetate (100 ml). The BSAsolution was filtered through a glass microfiber filter and added to thestirred 5-OCF₃ or 5*-OCF₃ solution in one portion. The mixture waswarmed to 60-65° C.; precipitation of the 18-OCF₃ or 18*-OCF₃ occurredduring the warm up period. The slurry was held for 60 minutes at 60-65°C. The suspension was allowed to slowly cool to 22° C. and was stirredat 20-25° C. for 16 hours. n-Heptane (920 ml) was charged in one portionand the suspension was stirred at 22° C. for an additional 90 minutes.The slurry was filtered and the collected solids washed with n-heptane(250 ml). The isolated solids were placed in a vacuum oven at 50° C. for16 hours. 52.26 g (86% yield) of 18-OCF₃ or 18*-OCF₃ benzenesulfonatewas obtained.

¹H NMR (400 MHz, DMSO-d6+D₂0): 89.16 (s, 1H), 8.95 (d, J=2.1 Hz, 1H),8.26 (dd, J=8.2, 2.3 Hz, 1H), 7.96-7.89 (m, 2H), 7.66-7.61 (m, 2H), 7.59(dd, J=8.3, 0.4 Hz, 1H), 7.53 (br d, J=8.0 Hz, 2H), 7.38-7.15 (m, 5H),6.90 (dt, J=8.3, 2.5 Hz, 1H), 5.69 (d, J=14.8 Hz, 1H), 5.15 (d, J=15.2Hz, 1H).

18-OCF₃/ 5-OCF₃/5*- 18-OCF₃/18*- 18-OCF₃/18*- 18*- 5-OCF₃/5*- OCF₃ OCF₃OCF₃ OCF₃ OCF₃ (%) (% ee) Yield Purity (%) ee 97.9 95.9 84% 98.2 97.1

Incorporation by Reference

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference.

Equivalents

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents of the specificembodiments of the invention described herein. Such equivalents areintended with be encompassed by the following claims.

1. A process to prepare a compound of Formula 1 or 1*, or mixturethereof:

the process comprising reacting a compound of Formula 2:

with nitromethane in the presence of a chiral catalyst of Formula 3:

wherein R₄ is H, optionally substituted alkyl, (C═O)-optionallysubstituted alkyl, (C═O)-optionally substituted aryl; and R₅ is H,optionally substituted alkyl, optionally substituted arylalkyl, oroptionally substituted aryl; to provide a compound of Formula 1 or 1*,or mixture thereof; wherein each R is independently halo, —O(C═O)-alkyl,—O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl,—O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl,—O(C═O)—O-substituted aryl, —O(SO₂)-alkyl, —O(SO₂)-substituted alkyl,—O(SO₂)-aryl, —O(SO₂)-substituted aryl,


2. The process of claim 1, further comprising enriching the enantiomericpurity of an enantiomeric compound mixture of Formula 1 and 1*,comprising: crystallizing said enantiomeric compound mixture with achiral acid in a suitable solvent or solvent mixture, wherein: thesuitable solvent or solvent mixture is selected from acetonitrile,isopropanol, ethanol, water, methanol, or combinations thereof; (ii)isolating the enantio-enriched chiral salt mixture; and (iii)free-basing the enantio-enriched chiral salt mixture to provide theenantio-enriched compound mixture.
 3. The process of claim 2, furthercomprising reslurrying the enantio-enriched chiral salt mixture in aslurrying solvent or slurrying solvent mixture.
 4. (canceled)
 5. Theprocess of claim 3, wherein the slurrying solvent or slurrying solventmixture is a) acetonitrile or b) a mixture of acetonitrile and methanol.6. The process of claim 4, wherein the mixture of acetonitrile andmethanol comprises 80-90% acetonitrile and 10-20% methanol.
 7. Theprocess of claim 5, wherein the mixture of acetonitrile and methanolcomprises 80-90% acetonitrile and 10-20% methanol.
 8. The process ofclaim 2, wherein the chiral acid is selected from the group consistingof tartaric acid, di-benzoyltartaric acid, malic acid, camphoric acid,camphorsulfonic acid, ascorbic acid, and di-p-toluoyltartaric acid. 9.(canceled)
 10. The process of claim 1, wherein the chiral catalyst is


11. The process of claim 10, wherein the mole percent of the chiralcatalyst is selected from about 0.5-50, about 0.5-25, about 1-10, and isabout
 5. 12-14. (canceled)
 15. The process of claim 1, wherein thenumber of equivalents of nitromethane is selected from about 1-25, about5-15, and about
 10. 16-17. (canceled)
 18. The process of claim 1,further comprising reducing a compound of Formula 1 or 1*, or mixturethereof:

to afford a compound of Formula 4 or 4*, or mixture thereof:

wherein each R is independently halo, —O(C═O)-alkyl, —O(C═O)-substitutedalkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl,—O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl,—O(SO₂)-alkyl, —O(SO₂)-substituted alkyl, —O(SO₂)-aryl,—O(SO₂)-substituted aryl,


19. The process of claim 18, further comprising enriching theenantiomeric purity of an enantiomeric compound mixture of Formula 1 and1* and/or enriching the enantiomeric purity of an enantiomeric compoundmixture of Formula 4 and 4*, comprising: crystallizing said enantiomericcompound mixture with a chiral acid in a suitable solvent or solventmixture, wherein: the suitable solvent or solvent mixture is selectedfrom acetonitrile, isopropanol, ethanol, water, methanol, orcombinations thereof; (ii) isolating the enantio-enriched chiral saltmixture; and (iii) free-basing the enantio-enriched chiral salt mixtureto provide the enantio-enriched compound mixture.
 20. The process ofclaim 18, further comprising reslurrying the enantio-enriched chiralsalt mixture in a slurrying solvent or slurrying solvent mixture. 21.(canceled)
 22. The process of claim 19, wherein the slurrying solvent orslurrying solvent mixture is a) acetonitrile or b) a mixture ofacetonitrile and methanol.
 23. The process of claim 20, wherein themixture of acetonitrile and methanol comprises 80-90% acetonitrile and10-20% methanol.
 24. The process of claim 21, wherein the mixture ofacetonitrile and methanol comprises 80-90% acetonitrile and 10-20%methanol.
 25. The process of claim 19, wherein the chiral acid isselected from the group consisting of tartaric acid, di-benzoyltartaricacid, malic acid, camphoric acid, camphorsulfonic acid, ascorbic acid,and di-p-toluoyltartaric acid.
 26. (canceled)
 27. A process to prepare acompound of Formula 5 or 5*, or mixture thereof:

the method comprising: (a) reacting a compound of Formula 6:

with nitromethane in the presence of a chiral catalyst of Formula 3:

to provide a compound of Formula 7 or 7*, or mixture thereof; and

(b) conversion of a compound of Formula 7 or 7*, or mixture thereof, toa compound of Formula 5 or 5*, or mixture thereof; wherein each R₂ isindependently OCF₃ or OCH₂CF₃; each R₃ is independently halo,—O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl,—O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl,—O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO₂)-alkyl,—O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or —O(SO₂)-substituted aryl;each R₄ is H, optionally substituted alkyl, (C═O)-optionally substitutedalkyl, (C═O)-optionally substituted aryl; and R₅ is H, optionallysubstituted alkyl, optionally substituted arylalkyl, or optionallysubstituted aryl.
 28. The process of claim 27, further comprising: (c)amidation of ester 9;

to afford morpholine amide 10; and

(d) arylation of morpholine amide 10 to afford ketone 6;

wherein each R₃ is independently halo, —O(C═O)-alkyl,—O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl,—O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl,—O(C═O)—O-substituted aryl, —O(SO₂)-alkyl, —O(SO₂)-substituted alkyl,—O(SO₂)-aryl, or —O(SO₂)-substituted aryl.
 29. The process of claim 28,wherein step (d) comprises reacting morpholine amide 10,

wherein M is Mg or MgX, Li, AlX₂; and X is halogen, alkyl, or aryl; andR₃ is independently halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl,—O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl,—O(C═O)—O-substituted alkyl, —O(C═O)-O-aryl, —O(C═O)—O-substituted aryl,—O(SO₂)-alkyl, —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or—O(SO₂)-substituted aryl.
 30. The process of claim 29, wherein M is Mgor MgX, and X is halogen.
 31. The process of claim 27, furthercomprising (c) reducing a compound of Formula 7 or 7*, or mixturethereof:

to afford a compound of Formula 11 or 11*, or mixture thereof:

wherein each R₃ is independently halo, —O(C═O)-alkyl,—O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl,—O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl,—O(C═O)—O-substituted aryl, —O(SO₂)-alkyl, —O(SO₂)-substituted alkyl,—O(SO₂)-aryl, or —O(SO₂)-substituted aryl.
 32. The process of claim 31,further comprising: (f) arylating a compound of Formula 11 or 11*, ormixture thereof;

to afford a compound of Formula 12 or 12*, or mixture thereof; and

(g) forming the tetrazole of a compound of Formula 12 or 12*, or mixturethereof, to afford a compound of Formula 5 or 5*, or mixture thereof;

wherein each R₂ is independently OCF₃ or OCH₂CF₃; and each R₃ isindependently halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl,—O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl,—O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl,—O(SO₂)-alkyl, —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or—O(SO₂)-substituted aryl.
 33. The process of claim 31, furthercomprising: (h) forming the tetrazole of a compound of Formula 11 or11*, or mixture thereof;

to afford a compound of Formula 13 or 13*, or mixture thereof; and

(i) arylating a compound of Formula 13 or 13*, or mixture thereof, toafford a compound of Formula 5 or 5*, or mixture thereof;

wherein each R₂ is independently OCF₃ or OCH₂CF₃; and each R₃ isindependently halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl,—O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl,—O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl,—O(SO₂)-alkyl, —O(SO₂)-substituted alkyl, —O(SO₂)-aryl, or—O(SO₂)-substituted aryl.
 34. The process of claim 31, furthercomprising enriching the enantiomeric purity of an enantiomeric compoundmixture of Formula 7 and 7* and/or enriching the enantiomeric purity ofan enantiomeric compound mixture of Formula 11 and 11*, comprising:crystallizing said enantiomeric compound mixture with a chiral acid in asuitable solvent or solvent mixture, wherein: the suitable solvent orsolvent mixture is selected from acetonitrile, isopropanol, ethanol,water, methanol, or combinations thereof; (ii) isolating theenantio-enriched chiral salt mixture; and (iii) free-basing theenantio-enriched chiral salt mixture to provide the enantio-enrichedcompound mixture.
 35. The process of claim 34, further comprisingreslurrying the enantio-enriched chiral salt mixture in a slurryingsolvent or slurrying solvent mixture.
 36. (canceled)
 37. The process ofclaim 35, wherein the slurrying solvent or slurrying solvent mixture isa) acetonitrile or b) a mixture of acetonitrile and methanol.
 38. Theprocess of claim 36, wherein the mixture of acetonitrile and methanolcomprises 80-90% acetonitrile and 10-20% methanol.
 39. The process ofclaim 37, wherein the mixture of acetonitrile and methanol comprises80-90% acetonitrile and 10-20% methanol.
 40. The process of claim 34,wherein the chiral acid is selected from the group consisting oftartaric acid, di-benzoyltartaric acid, malic acid, camphoric acid,camphorsulfonic acid, ascorbic acid, and di-p-toluoyltartaric acid. 41.(canceled)
 42. The process of claim 27, wherein the chiral catalyst is


43. The process of claim 42, wherein the mole percent of the chiralcatalyst is selected from about 0.5-50, about 0.5-25, about 1-10, andabout
 5. 44-46. (canceled)
 47. The process of claim 27, wherein thenumber of equivalents of nitromethane is selected from about 1-25, about5-15, and about
 10. 48-49. (canceled)